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Clinical trials (London, England)  2014;11(3):362-375.
The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results.
To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and determine definitively if testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions.
We present the scientific and clinical rationale for the decisions made in the design of this trial.
We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and also symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, treatment and monitoring and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data safety monitoring board (DSMB), the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in subject selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary end points for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation.
Potential Limitations
Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one subject.
The Testosterone Trials were designed to determine definitively if testosterone treatment of elderly men with low testosterone would have any clinical benefit. Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.
PMCID: PMC4182174  PMID: 24686158
clinical trial; testosterone; hypogonadism; aging; mobility; sexual function; vitality; cognitive function; anemia; CT angiography; volumetric BMD; bone strength
3.  Comparison of younger and older breast cancer survivors and age-matched controls on specific and overall QoL domains 
Cancer  2014;120(15):2237-2246.
Younger survivors (YS) of breast cancer often report more survivorship symptoms such as fatigue, depression, sexual difficulty, and cognitive problems than older survivors (OS). We sought to determine the effect of breast cancer and age at diagnosis on Quality of Life (QoL) by comparing 3 groups: 1) YS diagnosed at age 45 or before, 2) OS diagnosed between 55 and 70, and, 3) for the YS, age-matched controls (AC) of women not diagnosed with breast cancer.
Using a large Eastern Cooperative Oncology Group (ECOG) data base, we recruited 505 YS who were ages 45 or younger when diagnosed and 622 OS diagnosed at 55 to 70. YS, OS, and AC were compared on physical, psychological, social, spiritual, and overall QoL variables.
Compared to both AC and to OS, YS reported more depressive symptoms (p=.005) and fatigue (p<.001), poorer self-reported attention function (p<.001), and poorer sexual function (p<.001) than either comparison group. However, YS also reported a greater sense of personal growth (p<.001) and perceived less social constraint (p<.001) from their partner than AC.
YS reported worse functioning than AC relative to depression, fatigue, attention, sexual function, and spirituality. Perhaps even more important, YS fared worse than both AC and OS on body image, anxiety, sleep, marital satisfaction, and fear of recurrence, indicating that YS are at greater risk for long term QoL problems than survivors diagnosed at a later age.
PMCID: PMC4158315  PMID: 24891116
Young survivors; Quality of Life; Breast Cancer; Comparison of Younger; Comparison of Older Survivors
4.  Validity and reliability of the Patient-Reported Arthralgia Inventory: validation of a newly-developed survey instrument to measure arthralgia 
There is a need for a survey instrument to measure arthralgia (joint pain) that has been psychometrically validated in the context of existing reference instruments. We developed the 16-item Patient-Reported Arthralgia Inventory (PRAI) to measure arthralgia severity in 16 joints, in the context of a longitudinal cohort study to assess aromatase inhibitor-associated arthralgia in breast cancer survivors and arthralgia in postmenopausal women without breast cancer. We sought to evaluate the reliability and validity of the PRAI instrument in these populations, as well as to examine the relationship of patient-reported morning stiffness and arthralgia.
We administered the PRAI on paper in 294 women (94 initiating aromatase inhibitor therapy and 200 postmenopausal women without breast cancer) at weeks 0, 2, 4, 6, 8, 12, 16, and 52, as well as once in 36 women who had taken but were no longer taking aromatase inhibitor therapy.
Cronbach’s alpha was 0.9 for internal consistency of the PRAI. Intraclass correlation coefficients of test-retest reliability were in the range of 0.87–0.96 over repeated PRAI administrations; arthralgia severity was higher in the non-cancer group at baseline than at subsequent assessments. Women with joint comorbidities tended to have higher PRAI scores than those without (estimated difference in mean scores: −0.3, 95% confidence interval [CI] −0.5, −0.2; P<0.001). The PRAI was highly correlated with the Functional Assessment of Cancer Therapy-Endocrine Subscale item “I have pain in my joints” (reference instrument; Spearman r range: 0.76–0.82). Greater arthralgia severity on the PRAI was also related to decreased physical function (r=−0.47, 95% CI −0.55, −0.37; P<0.001), higher pain interference (r=0.65, 95% CI 0.57–0.72; P<0.001), less active performance status (estimated difference in location (−0.6, 95% CI −0.9, −0.4; P<0.001), and increased morning stiffness duration (r=0.62, 95% CI 0.54–0.69; P<0.0001).
We conclude that the psychometric properties of the PRAI are satisfactory for measuring arthralgia severity.
PMCID: PMC4524452  PMID: 26251635
arthralgia; joint pain; pain measurement; validation studies; questionnaire design; aromatase inhibitors; postmenopause
5.  Calibration and Validation of the Dutch-Flemish PROMIS Pain Interference Item Bank in Patients with Chronic Pain 
PLoS ONE  2015;10(7):e0134094.
The Dutch-Flemish PROMIS Group translated the adult PROMIS Pain Interference item bank into Dutch-Flemish. The aims of the current study were to calibrate the parameters of these items using an item response theory (IRT) model, to evaluate the cross-cultural validity of the Dutch-Flemish translations compared to the original English items, and to evaluate their reliability and construct validity. The 40 items in the bank were completed by 1085 Dutch chronic pain patients. Before calibrating the items, IRT model assumptions were evaluated using confirmatory factor analysis (CFA). Items were calibrated using the graded response model (GRM), an IRT model appropriate for items with more than two response options. To evaluate cross-cultural validity, differential item functioning (DIF) for language (Dutch vs. English) was examined. Reliability was evaluated based on standard errors and Cronbach’s alpha. To evaluate construct validity correlations with scores on legacy instruments (e.g., the Disabilities of the Arm, Shoulder and Hand Questionnaire) were calculated. Unidimensionality of the Dutch-Flemish PROMIS Pain Interference item bank was supported by CFA tests of model fit (CFI = 0.986, TLI = 0.986). Furthermore, the data fit the GRM and showed good coverage across the pain interference continuum (threshold-parameters range: -3.04 to 3.44). The Dutch-Flemish PROMIS Pain Interference item bank has good cross-cultural validity (only two out of 40 items showing DIF), good reliability (Cronbach’s alpha = 0.98), and good construct validity (Pearson correlations between 0.62 and 0.75). A computer adaptive test (CAT) and Dutch-Flemish PROMIS short forms of the Dutch-Flemish PROMIS Pain Interference item bank can now be developed.
PMCID: PMC4516300  PMID: 26214178
6.  Factors Associated With Grade 3-4 Treatment-Related Toxicity In Women With Advanced Or Recurrent Cervical Cancer: An Exploratory Analysis Of NRG Oncology/Gynecologic Oncology Group Trials (GOG) 179 And 204 
To describe pretreatment patient characteristics and baseline quality of life (QoL) scores as they relate to the development of grade 3-4 toxicity in patients receiving chemotherapy for advanced/recurrent cervical cancer.
The study sample was drawn from Gynecologic Oncology Group (GOG) protocols 179 and 204. Grade 3 or 4 toxicities were considered in four specified categories: peripheral neuropathy, fatigue, hematologic and gastrointestinal. The data variables explored included age, stage, pretreatment radiation, performance status (PS) at treatment initiation and baseline FACT-Cx (Functional Assessment of Cancer Therapy-Cervix) score. A logistic regression model was developed with various adverse events as binary [0/1] outcomes.
Six-hundred-seventy-three patient-reported questionnaires were used in the analyses. At baseline, pain was the most severe patient-reported symptom. Baseline line-item patient concerns did demonstrate specific correlations with the development of individual toxicities. In 401 patients were enrolled on GOG 204 (fatigue not measured on 179), a worse PS predicted the development of grade 3-4 fatigue (OR 2.78 95% CI 1.66-4.68). Exposure to prior radiation, treatment regimen and a worse FACT-Cx score were associated with the reporting of both grade 3-4 leukopenia (P<0.05) and anemia (p<.0005). PS and treatment regimen (p<0.05) were associated with the development of grade 3-4 thrombocytopenia. Age and treatment regimen (p<0.05) were associated with the development of grade 3-4 neutropenia. The FACT-Cx score (p=0.0016) predicted grade 3-4 GI toxicity.
The development of fatigue, hematologic and GI toxicity might be predictable based on factors other than treatment assignment such as age, PS and patient-reported QoL measurement.
PMCID: PMC4506195  PMID: 25405577
Quality of life; Gynecologic Oncology Group; cervical cancer; grade 3; grade 4; toxicity
7.  Recommended Patient-Reported Core Set of Symptoms and Quality-of-Life Domains to Measure in Ovarian Cancer Treatment Trials 
There is no consensus as to what symptoms or quality-of-life (QOL) domains should be measured as patient-reported outcomes (PROs) in ovarian cancer clinical trials. A panel of experts convened by the National Cancer Institute reviewed studies published between January 2000 and August 2011. The results were included in and combined with an expert consensus-building process to identify the most salient PROs for ovarian cancer clinical trials. We identified a set of PROs specific to ovarian cancer: abdominal pain, bloating, cramping, fear of recurrence/disease progression, indigestion, sexual dysfunction, vomiting, weight gain, and weight loss. Additional PROs identified in parallel with a group charged with identifying the most important PROs across cancer types were anorexia, cognitive problems, constipation, diarrhea, dyspnea, fatigue, nausea, neuropathy, pain, and insomnia. Physical and emotional domains were considered to be the most salient domains of QOL. Findings of the review and consensus process provide good support for use of these ovarian cancer–specific PROs in ovarian cancer clinical trials.
PMCID: PMC4110471  PMID: 25006190
8.  Recommended Patient-Reported Core Set of Symptoms to Measure in Adult Cancer Treatment Trials 
The National Cancer Institute’s Symptom Management and Health-Related Quality of Life Steering Committee held a clinical trials planning meeting (September 2011) to identify a core symptom set to be assessed across oncology trials for the purposes of better understanding treatment efficacy and toxicity and to facilitate cross-study comparisons. We report the results of an evidence-synthesis and consensus-building effort that culminated in recommendations for core symptoms to be measured in adult cancer clinical trials that include a patient-reported outcome (PRO).
We used a data-driven, consensus-building process. A panel of experts, including patient representatives, conducted a systematic review of the literature (2001–2011) and analyzed six large datasets. Results were reviewed at a multistakeholder meeting, and a final set was derived emphasizing symptom prevalence across diverse cancer populations, impact on health outcomes and quality of life, and attribution to either disease or anticancer treatment.
We recommend that a core set of 12 symptoms—specifically fatigue, insomnia, pain, anorexia (appetite loss), dyspnea, cognitive problems, anxiety (includes worry), nausea, depression (includes sadness), sensory neuropathy, constipation, and diarrhea—be considered for inclusion in clinical trials where a PRO is measured. Inclusion of symptoms and other patient-reported endpoints should be well justified, hypothesis driven, and meaningful to patients.
This core set will promote consistent assessment of common and clinically relevant disease- and treatment-related symptoms across cancer trials. As such, it provides a foundation to support data harmonization and continued efforts to enhance measurement of patient-centered outcomes in cancer clinical trials and observational studies.
PMCID: PMC4110472  PMID: 25006191
9.  Spiritual well-being and health-related quality of life in colorectal cancer: a multi-site examination of the role of personal meaning 
Individuals diagnosed and treated for cancer often report high levels of distress, continuing even after successful treatment. Spiritual well-being (SpWB) has been identified as an important factor associated with positive health outcomes. This study had two aims: (1) examine the associations between SpWB (faith and meaning/peace) and health-related quality of life (HRQL) outcomes and (2) examine competing hypotheses of whether the relationship among distress, SpWB, and HRQL is better explained by a stress-buffering (i.e., interaction) or a direct (main effects) model.
Study 1 consisted of 258 colorectal cancer survivors (57% men) recruited from comprehensive cancer centers in metropolitan areas (age, M=61; months post-diagnosis, M=17). Study 2 consisted of 568 colorectal cancer survivors (49% men) recruited from a regional cancer registry (age, M=67; months post-diagnosis, M=19). Participants completed measures of SpWB (Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp)) and HRQL (Functional Assessment of Cancer Therapy-Colorectal) in both studies. Measures of general distress (Profile of Mood States-Short Form) and cancer-specific distress were also completed in study 1 and study 2, respectively.
After controlling for demographic and clinical variables, faith and meaning/peace were positively associated with HRQL. However, meaning/peace emerged as a more robust predictor of HRQL outcomes than faith. Planned analyses supported a direct rather than stress-buffering effect of meaning/peace.
This study provides further evidence of the importance of SpWB, particularly meaning/peace, to HRQL for people with colorectal cancer. Future studies of SpWB and cancer should examine domains of the FACIT-Sp separately and explore the viability of meaning-based interventions for cancer survivors.
PMCID: PMC4474154  PMID: 20405147
Spiritual well-being; Quality of life; Meaning; Peace; Faith; Cancer
10.  A Randomized Phase III Trial in Advanced Endometrial Carcinoma of Surgery and Volume Directed Radiation Followed by Cisplatin and Doxorubicin with or without Paclitaxel: A Gynecologic Oncology Group Study 
Gynecologic oncology  2008;112(3):543-552.
After surgical debulking and volume-directed irradiation of the pelvis/para-aortic lymph nodes, treatment was randomized to compare recurrence-free survival (RFS) and toxicity between two chemotherapy regimens for the treatment of women with advanced stage endometrial carcinoma.
Treatment was randomized between 6 cycles of cisplatin [C] (50 mg/m2) and doxorubicin [D] (45 mg/m2) with or without paclitaxel [P] (160 mg/m2). Initially in paclitaxel treated patients and, after May 2002, all patients received granulocyte growth factor with each cycle.
Of 659 patients enrolled following surgery, 552 eligible patients were randomized to chemotherapy after irradiation. Accrual closed to Stage IV patients in June, 2003. Approximately 80% completed six cycles of chemotherapy. Three deaths resulted from bowel complications and one death was due to renal failure. Hematologic adverse events, sensory neuropathy and myalgia, were more frequent and severe in the paclitaxel arm (p< 0.01) which was confirmed by Quality of Life assessments. Percentage of patients alive and recurrence-free at 36 months was 62% for CD vs. 64% for CDP. The hazard of recurrence or death relative to the CD arm stratified by stage is 0.90 (95% CI is 0.69 to 1.17, p=0.21, one-tail). However, in subgroup analysis, CDP was associated with a 50% reduction in the risk of recurrence or death among patients with gross residual disease (95% CI: 0.26 to 0.92). Stage, residual disease, histology/grade, positive para-aortic node and cytology, pelvic metastases and age were significantly associated with RFS.
The addition of paclitaxel to cisplatin and doxorubicin following surgery and radiation was not associated with a significant improvement in RFS but was associated with increased toxicity.
PMCID: PMC4459781  PMID: 19108877
Advanced Endometrial Carcinoma; Surgery; Radiation and Chemotherapy
11.  A Randomized Trial of Weekly Symptom Telemonitoring in Advanced Lung Cancer 
Lung cancer patients experience multiple, simultaneous symptoms related to their disease and treatment that impair functioning and health-related quality of life (HRQL). Computer technology can reduce barriers to nonsystematic, infrequent symptom assessment and potentially contribute to improved patient care.
To evaluate the efficacy of technology-based symptom monitoring and reporting in reducing symptom burden in patients with advanced lung cancer.
This was a prospective, multisite, randomized controlled trial (RCT). Two hundred fifty-three patients were enrolled at three sites and randomized to monitoring and reporting (MR) or monitoring alone (MA). Patients completed questionnaires at baseline, 3, 6, 9 and 12 weeks and symptom surveys via interactive voice response (IVR) weekly for 12 weeks. MR patients’ clinically significant symptom scores generated an e-mail alert to the site nurse for management. The primary endpoint was overall symptom burden; secondary endpoints included HRQL, treatment satisfaction, symptom management barriers, and self-efficacy.
This RCT failed to demonstrate efficacy of symptom monitoring and reporting in reducing symptom burden compared with monitoring alone in lung cancer. HRQL declined over 12 weeks in both groups (P<0.006 to P<0.025); at week 12, treatment satisfaction was higher in MA than MR patients (P<0.012, P<0.027). Adherence to weekly calls was good (82%) and patient satisfaction was high.
Feasibility of using a technology-based system for systematic symptom monitoring in advanced lung cancer patients was demonstrated. Future research should focus on identifying patients most likely to benefit and other patient, provider and health system factors likely to contribute to the system’s success.
PMCID: PMC4013267  PMID: 24210705
lung cancer; symptoms; randomized controlled trial; health information technology; telemonitoring
12.  Advances in Outcomes Measurement in Rehabilitation Medicine: Current Initiatives from the National Institutes of Health and the National Institute on Disability and Rehabilitation Research 
The articles in the current supplement present recent advances in measurement of patient-reported health related quality of life (HRQOL) outcomes. Specifically, these articles highlight combined efforts of the National Institutes of Health (NIH), National Institute for Neurological Disorders and Stroke (NINDS), National Center on Medical Rehabilitation Research (NCMRR), National Institute on Disability and Rehabilitation Research (NIDRR) and Department of Veterans Affairs Rehabilitation Research and Development Service (VA RR&D) to improve HRQOL measurement. Further, this supplement is intended to provide rehabilitation professionals with information about these efforts and the implications that these advances in outcomes measurement have in rehabilitation medicine and clinical practice. These new measurement scales utilize state-of-the-art methodology techniques including item response theory (IRT) and computerized adaptive testing (CAT). In addition, scale development involves both qualitative and quantitative methods, as well as the administration of items to hundreds or even thousands, of research participants. The scales have been deliberately built with overlap of items between scales so that linkages and equivalency scores can be computed. Ultimately, these scales should facilitate direct comparison of outcomes instruments across studies and will serve as standard data elements across research trials without compromising the specificity of disease- or condition-targeted measures. This supplement includes the initial publications for many of these new measurement initiatives, each of which provides researchers and clinicians with better tools for evaluation of the efficacy of their interventions.
PMCID: PMC4425123  PMID: 21958917
Quality of Life; Outcome Assessment (Health Care); Health-Related Quality of Life; Rehabilitation; Patient Reported Outcomes
13.  Parent-reported cognition of children with cancer and its potential clinical usefulness 
Cognitive dysfunction is a common concern for children with brain tumors (BTs) or those receiving central nervous system (CNS) toxic cancer treatments. Perceived cognitive function (PCF) is an economical screening that may be used to trigger full, formal cognitive testing. We assessed the potential clinical utility of PCF by comparing parent-reported scores for children with cancer with scores from the general US population.
Children (n = 515; mean age =13.5 years; 57.0 % male) and one of their parents were recruited from pediatric oncology clinics. Most children (53.3 %) had a diagnosis of CNS tumor with an average time since diagnosis of 5.6 years. PCF was evaluated using the pediatric PCF item bank (pedsPCF), which was developed and normed on a sample drawn from the US general pediatric population. Children also completed computer-based neuropsychological tests. We tested relationships between PCF and clinical variables. Differential item functioning (DIF) was used to evaluate measurement bias between the samples.
No item showed DIF, supporting the use of pedsPCF in the cancer sample. PedsPCF differentiated children with (vs. without) a BT, p < 0.01, and groups defined by years since diagnosis, p < 0.01. It significantly (p < 0.05) correlated with computerized neuropsychological tests in 40 of 60 comparisons. Children with BTs were rated as having worse pedsPCF scores than the norm, regardless of years since diagnosis.
PCF significantly differentiated cancer survivors with various clinical characteristics. It is brief and easy to implement. PCF should be considered for routine care of pediatric cancer survivors.
PMCID: PMC3967001  PMID: 24197478
Perceived cognitive function; Item bank; Pediatric cancer; Brain tumor; Item response theory; Quality of life
The objective of the current study was to improve the assessment of physical function by improving the precision of assessment at the floor (extremely poor function) and at the ceiling (extremely good health) of the health continuum.
Under the NIH PROMIS program, we developed new physical function floor and ceiling items to supplement the existing item bank. Using item response theory (IRT) and the standard PROMIS methodology, we developed 30 floor items and 26 ceiling items and administered them during a 12-month prospective observational study of 737 individuals at the extremes of health status. Change over time was compared across anchor instruments and across items by means of effect sizes. Using the observed changes in scores, we back-calculated sample size requirements for the new and comparison measures.
We studied 444 subjects with chronic illness and/or extreme age, and 293 generally fit subjects including athletes in training. IRT analyses confirmed that the new floor and ceiling items outperformed reference items (p<0.001). The estimated post-hoc sample size requirements were reduced by a factor of two to four at the floor and a factor of two at the ceiling.
Extending the range of physical function measurement can substantially improve measurement quality, can reduce sample size requirements and improve research efficiency. The paradigm shift from Disability to Physical Function includes the entire spectrum of physical function, signals improvement in the conceptual base of outcome assessment, and may be transformative as medical goals more closely approach societal goals for health.
PMCID: PMC4012831  PMID: 24782194
15.  Development and validation of the functional assessment of cancer therapy–antiangiogenesis subscale 
Cancer Medicine  2015;4(5):690-698.
The Functional Assessment of Cancer Therapy (FACT)–Antiangiogenesis (AntiA) Subscale was developed and validated to enhance treatment decision-making and side effect management for patients receiving anti-angiogenesis therapies. Side effects related to anti-angiogenesis therapies were identified from the literature, clinician input, and patient input. Fifty-nine possible patient expressions of side effects were generated. Patient and clinician ratings of the importance of these expressions led us to develop a 24-item questionnaire with clinical and research potential. To assess the scale's reliability and validity, 167 patients completed the AntiA Subscale, the Functional Assessment of Cancer Therapy-general (FACT-G), the FACT-Kidney Symptom Index (FKSI), the FACIT-Fatigue Subscale, the Global Rating of Change Scale (GRC), and the PROMIS Global Health Scale. Patient responses to the AntiA were analyzed for internal consistency, test–retest reliability, convergent and discriminant validity, and responsiveness to change in clinical status. All tested scales were found to have good internal consistency reliability (Cronbach's alpha 0.70–0.92). Test–retest reliability was also good (0.72–0.88) for total and subscale scores and lower for individual items. The total score, subscale scores, and all single items (except nosebleeds) significantly differentiated between groups defined by level of side effect bother. Evaluation of responsiveness to change in this study was not conclusive, suggesting an area for further research. The AntiA is a reliable and valid measure of side effects from anti-angiogenesis therapy.
PMCID: PMC4430262  PMID: 25619758
antiangiogenesis; cancer; patient-reported outcomes; quality of life; side effects
17.  Demographic Differences in Health Preferences in the United States 
Medical care  2014;52(4):307-313.
The United States has a culturally and demographically diverse populace, and the aim of this study was to examine differences in health preferences by gender, age, ethnicity, and race.
We assessed preferences for health outcomes defined by the PROMIS-29 survey in a sample of the U.S. population. Based on the survey’s 540 paired comparisons trading off lifespan and 7 domains of health-related quality of life (HRQoL), we compared the choices between men and women, adults age 18 to 54 years and 55 years and older, Hispanics and non-Hispanics and non-Hispanic Blacks and Whites. For each subgroup, we estimated the value of 122 HRQoL outcomes on a quality-adjusted life year (QALY) scale and tested for subgroup differences.
Compared to men, women preferred reduced lifespan over losses in HRQoL, particularly for depression. Compared to the younger adults, older adults preferred reduced lifespan over the symptoms of depression, anxiety, and fatigue. Compared to non-Hispanic Whites, Hispanics preferred reduced lifespan over depression and sleep disturbance, but held similar values on losses in physical functioning. Among non-Hispanics, Blacks preferred reduced lifespan over losses in ability to climb stairs and to fall asleep compared to Whites, but held similar values on mental health outcomes.
With the growing emphasis on patient-centeredness and culturally sensitive treatment, it is important to recognize the diversity in values placed on potential losses in HRQoL, particularly mental health outcomes. Demographic differences in preferences may influence comparative or cost effectiveness of treatments as perceived by one or another subgroup.
PMCID: PMC4031273  PMID: 24374420
Quality-adjusted life years; discrete choice experiments; patient-reported outcomes; preferences; Health-related Quality of Life (HRQoL)
18.  Predictors of Significant Worsening of Patient-Reported Fatigue over a One-Month Timeframe in Ambulatory Patients with Common Solid Tumors 
Cancer  2013;120(3):442-450.
Understanding the determinants of fatigue worsening may help distinguish between different fatigue phenotypes and inform clinical trial designs.
Patients and Methods
Patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled from multiple sites. At enrollment during an outpatient visit and 4–5 weeks later patients rated their symptoms on a 0–10 numerical rating scale. A 2-point change was considered clinically significant for fatigue change. Effects of demographic and clinical factors on patient-reported fatigue were examined using logistic regression models.
3123 patients were enrolled at baseline and 3032 were analyzable for fatigue change. At baseline, 23% had no fatigue, 35% mild, 25% moderate, and 17% severe. Key parameters in our model of fatigue worsening includes fatigue at baseline (OR 0.75), disease status (OR 1.99), performance status (OR 1.38), history of depression (OR 1.28), patient perception of bother due to comorbidity (OR 1.26) and treatment exposures including recent cancer treatment (OR 1.77), and use of corticosteroids (1.37). The impact of gender was examined only in colorectal and lung cancer patients, and it was a significant factor with men most likely to experience worsening of fatigue (OR=1.46).
Predictors of fatigue worsening include multiple factors that are difficult to modify: baseline fatigue level, gender, disease status, performance status, recent cancer treatment, bother due to comorbidity, and history of depression. Future fatigue prevention and treatment trial designs should account for key predictors of worsening fatigue.
PMCID: PMC4134680  PMID: 24151111
cancer fatigue; symptom management; medical oncology; ambulatory care
19.  A Literature Synthesis of Symptom Prevalence and Severity in Persons Receiving Active Cancer Treatment 
Patients with cancer experience acute and chronic symptoms caused by their underlying disease or by the treatment. While numerous studies have examined the impact of various treatments on symptoms experienced by cancer patients, there are inconsistencies regarding the symptoms measured and reported in treatment trials. This article presents a systematic review of the research literature of the prevalence and severity of symptoms in patients undergoing cancer treatment.
A systematic search for studies of persons receiving active cancer treatment was performed with the search terms of “multiple symptoms” and “cancer” for studies involving patients over the age of 18 years and published in English during the years 2001 to 2011. Search outputs were reviewed independently by seven authors, resulting in the synthesis of 21 studies meeting criteria for generation of an Evidence Table reporting symptom prevalence and severity ratings.
Data were extracted from 21 multi-national studies to develop a pooled sample of 4067 cancer patients in whom the prevalence and severity of individual symptoms was reported. In total, the pooled sample across the 21 studies was comprised of 62% female, with a mean age of 58 years (range: 18 to 97 years). A majority (62%) of these studies assessed symptoms in homogeneous samples with respect to tumor site (predominantly breast and lung cancer), while 38% of the included studies utilized samples with mixed diagnoses and treatment regimens. Eighteen instruments and structured interviews were including those measuring single symptoms, multi-symptom inventories, and single symptom items drawn from HRQOL or health status measures. The MD Anderson Symptom Inventory (MDASI) was the most commonly used instrument in the studies analyzed (n=9 studies; 43%), while the Functional Assessment of Cancer Therapy (FACT-G), Hospital Anxiety and Depression Subscale (HADS-D), Medical Outcomes Survey Short Form-36 (SF-36), and Symptom Distress Scale (SDS) were each employed in two studies. Forty-seven symptoms were identified across the 21 studies which were then categorized into 17 logical groupings. Symptom prevalence and severity were calculated across the entire cohort and also based upon sample sizes in which the symptoms were measured providing the ability to rank symptoms.
Symptoms are prevalent and severe among patients with cancer. Therefore, any clinical study seeking to evaluate the impact of treatment on patients should consider including measurement of symptoms. This study demonstrates that a discrete set of symptoms is common across cancer types. This set may serve as the basis for defining a “core” set of symptoms to be recommended for elicitation across cancer clinical trials, particularly among patients with advanced disease.
PMCID: PMC4299699  PMID: 23314601
Cancer; symptoms; systematic review
20.  Establishing a Common Metric for Self-Reported Anxiety: Linking the MASQ, PANAS, and GAD-7 to PROMIS Anxiety 
Journal of anxiety disorders  2013;28(1):88-96.
Researchers and clinicians wishing to assess anxiety must choose from among numerous assessment options, many of which purport to measure the same or a similar construct. A common reporting metric would have great value, and can be achieved when similar instruments are administered to a single sample and then linked to each other to produce cross-walk score tables. Using item response theory (IRT), we produced cross-walk tables linking three popular “legacy” anxiety instruments – MASQ (N = 743), GAD-7 (N = 748), and PANAS (N = 1120) – to the anxiety metric of the NIH Patient Reported Outcomes Measurement Information System (PROMIS®). The linking relationships were evaluated by resampling small subsets and estimating confidence intervals for the differences between the observed and linked PROMIS scores. Our results allow clinical researchers to retrofit existing data of three commonly-used anxiety measures to the PROMIS Anxiety metric and to compare clinical cut-off scores.
PMCID: PMC4046852  PMID: 24508596
anxiety; linking; PROMIS; MASQ; GAD-7; PANAS
21.  Intracerebral Hemorrhage and Delirium Symptoms. Length of Stay, Function, and Quality of Life in a 114-Patient Cohort 
Rationale: The prognostic significance of delirium symptoms in intensive care unit (ICU) patients with focal neurologic injury is unclear.
Objectives: To determine the relationship between delirium symptoms and subsequent functional outcomes and quality of life (QOL) after intracerebral hemorrhage.
Methods: We prospectively enrolled 114 patients. Delirium symptoms were routinely assessed twice daily using the Confusion Assessment Method for the ICU by trained nurses. Functional outcomes were recorded with modified Rankin Scale (scored from 0 [no symptoms] to 6 [dead]), and QOL outcomes with Neuro-QOL at 28 days, 3 months, and 12 months.
Measurements and Main Results: Thirty-one (27%) patients had delirium symptoms (“ever delirious”), 67 (59%) were never delirious, and the remainder (14%) had persistent coma. Delirium symptoms were nearly always hypoactive, were detected mean 6 days after intracerebral hemorrhage presentation, and were associated with longer ICU length of stay (mean 3.5 d longer in ever vs. never delirious patients; 95% confidence interval, 1.5–8.3; P = 0.004) after correction for age, admit National Institutes of Health (NIH) Stroke Scale, and any benzodiazepine exposure. Delirium symptoms were associated with increased odds of poor outcome at 28 days (odds ratio, 8.7; 95% confidence interval, 1.4–52.5; P = 0.018) after correction for admission NIH Stroke Scale and age, and with worse QOL in the domains of applied cognition–executive function and fatigue after correcting for the NIH Stroke Scale, age, benzodiazepine exposure, and time of follow-up.
Conclusions: After focal neurologic injury, delirium symptoms were common despite low rates of infection and sedation exposure, and were predictive of subsequent worse functional outcomes and lower QOL.
PMCID: PMC3919076  PMID: 24102675
delirium; outcomes; quality of life
22.  Characterizing fatigue associated with sunitinib and its impact on health-related quality of life in patients with metastatic renal cell carcinoma 
Cancer  2014;120(12):1871-1880.
Using phase 3 trial data for sunitinib versus interferon (IFN)-α in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life (HRQoL).
Patients received sunitinib at a dose of 50 mg/day on a schedule of 4 weeks on/2 weeks off (375 patients) or IFN-α at a dose of 9 MU subcutaneously 3 times per week (360 patients). HRQoL was self-assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom Index–15-item (FKSI-15) questionnaire, with fatigue assessed using its Disease-Related Symptoms subscale. Fatigue was also assessed by providers using Common Terminology Criteria for Adverse Events (CTCAE). A repeated-measures model (M1) and random intercept-slope model (M2) characterized sunitinib-associated fatigue over time. Another repeated-measures model examined the relationship between HRQoL scores and CTCAE fatigue grade.
M1 demonstrated that the initial increase in patient-reported fatigue with sunitinib was worst during cycle 1, with mean values numerically better at subsequent cycles; most pairwise comparisons of consecutive CTCAE fatigue cycle means were not found to be statistically significant. M2 demonstrated that the overall trend (slope) for patient-reported and CTCAE fatigue with sunitinib was not statistically different from 0. The relationship between most HRQoL scores and CTCAE fatigue was close to linear regardless of treatment, with lower scores (worse HRQoL) corresponding to higher fatigue grade. The majority of HRQoL scores were better with sunitinib versus IFN-α for the same CTCAE fatigue grade.
Patients reported worse fatigue during the first sunitinib cycle. However, in subsequent consecutive cycles, less fatigue was reported with no statistically significant worsening. CTCAE fatigue assessment may not fully capture patient treatment experience. Cancer 2014;120:1871–1880. © 2014 American Cancer Society.
Using phase 3 trial data for sunitinib versus interferon-α in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life. Patients reported worse fatigue during the first sunitinib cycle, but in subsequent consecutive cycles less fatigue was reported with no statistically significant worsening; provider-assessed fatigue did not appear to fully capture patient treatment experience.
PMCID: PMC4231253  PMID: 24634003
sunitinib; metastatic renal cell carcinoma; fatigue; health-related quality of life; phase 3
23.  Development and validation of the positive affect and well-being scale for the neurology quality of life (Neuro-QOL) measurement system 
To develop and validate an item-response theory-based patient-reported outcomes assessment tool of positive affect and well-being (PAW). This is part of a larger NINDS-funded study to develop a health-related quality of life measurement system across major neurological disorders, called Neuro-QOL.
Informed by a literature review and qualitative input from clinicians and patients, item pools were created to assess PAW concepts. Items were administered to a general population sample (N = 513) and a group of individuals with a variety of neurologic conditions (N = 581) for calibration and validation purposes, respectively.
A 23-item calibrated bank and a 9-item short form of PAW was developed, reflecting components of positive affect, life satisfaction, or an overall sense of purpose and meaning. The Neuro-QOL PAW measure demonstrated sufficient unidimensionality and displayed good internal consistency, test–retest reliability, model fit, convergent and discriminant validity, and responsiveness.
The Neuro-QOL PAW measure was designed to aid clinicians and researchers to better evaluate and understand the potential role of positive health processes for individuals with chronic neurological conditions. Further psychometric testing within and between neurological conditions, as well as testing in non-neurologic chronic diseases, will help evaluate the generalizability of this new tool.
PMCID: PMC3855608  PMID: 23526093
Positive affect; Psychological well-being; Quality of life; Measurement; Patient-reported outcomes; Neurological conditions
24.  Brief versions of the FACIT-fatigue and FAACT subscales for patients with non-small cell lung cancer cachexia 
Supportive Care in Cancer  2014;23(5):1355-1364.
Cancer anorexia-cachexia syndrome (CACS) is common in advanced cancer patients and associated with weight loss, fatigue, impaired quality of life (QoL), and poor prognosis. The goal of this project was to identify the most responsive items from two QoL measures in the ROMANA 2 (NCT01387282) phase III global study evaluating anamorelin HCl in the treatment of non-small cell lung cancer (NSCLC) cachexia: the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and the Functional Assessment of Anorexia/Cachexia Therapy (FAACT).
In the ROMANA 2 trial, 477 patients with unresectable stage III or IV NSCLC and cachexia were to be enrolled and randomized (2:1) to receive anamorelin HCl or placebo once daily for 12 weeks. All 203 patients who reached the week 12 visit at the time of data analysis were included. Co-primary endpoints were change from baseline in lean body mass and handgrip strength. QoL was a secondary outcome with FACIT-F and FAACT questionnaires administered at baseline and at weeks 3, 6, 9, and 12.
Two 4-item scales (fatigue/activity and appetite/eating) from the FACIT-F and FAACT questionnaires, respectively, demonstrated good internal consistency reliability, validity, and responsiveness (also referred to as the Simplified Evaluation of Fatigue (SEF) and Simplified Evaluation of Appetite (SEA), respectively). The estimated important difference for each scale was 1–2 points.
These brief scales provide the psychometric properties necessary to promote future research in NSCLC patients with CACS. Additional work should examine the clinical utility of these scales and their impact on treatment decision-making.
PMCID: PMC4376952  PMID: 25351456
Measurement; Anorexia; Cachexia; Fatigue; Quality of life
25.  Recommendations for High-Priority Research on Cancer-Related Fatigue in Children and Adults 
Over the past decades, some scientific progress has been made in understanding and treating cancer-related fatigue (CRF). However, three major problems have limited further progress: lack of agreement about measurement, inadequate understanding of the underlying biology, and problems in the conduct of clinical trials for CRF. This commentary reports the recommendations of a National Cancer Institute Clinical Trials Planning Meeting and an ongoing National Cancer Institute working group to address these problems so that high-priority research and clinical trials can be conducted to advance the science of CRF and its treatment. Recommendations to address measurement issues included revising the current case definition to reflect more rigorous criteria, adopting the Patient Reported Outcomes Measurement Information System fatigue scales as standard measures of CRF, and linking legacy measures to the scales. With regard to the biology of CRF, the group identified the need for longitudinal research to examine biobehavioral mechanisms underlying CRF and testing mechanistic hypotheses within the context of intervention research. To address clinical trial issues, recommendations included using only placebo-controlled trial designs. setting eligibility to minimize sample heterogeneity or enable subgroup analysis, establishing a CRF severity threshold for participation in clinical trials, conducting dissemination trials of efficacious interventions (such as exercise), and combining nonpharmacologic and pharmacologic interventions to exploit the potential synergy between these approaches. Accomplishing these goals has the potential to advance the science of CRF and improve the clinical management of this troubling symptom.
PMCID: PMC3888121  PMID: 24047960

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