Choosing appropriate patient-reported outcomes instrument for glaucoma research: a systematic review of vision instruments

PURPOSE: To identify vision Patient-Reported Outcomes instruments relevant to glaucoma and assess their content validity.

METHODS: MEDLINE, MEDLINE in Process, EMBASE and SCOPUS (to January 2009) were systematically searched. Observational studies or randomised controlled trials, published in English, reporting use of vision instruments in glaucoma studies involving adults were included. In addition, reference lists were scanned to identify additional studies describing development and/or validation to ascertain the final version of the instruments. Instruments' content was then mapped onto a theoretical framework, the World Health Organization International Classification of Functioning, Disability and Health. Two reviewers independently evaluated studies for inclusion and quality assessed instrument content.

RESULTS: Thirty-three instruments were identified. Instruments were categorised into thirteen vision status, two vision disability, one vision satisfaction, five glaucoma status, one glaucoma medication related to health status, five glaucoma medication side effects and six glaucoma medication satisfaction measures according to each instruments' content. The National Eye Institute Visual Function Questionnaire-25, Impact of Vision Impairment and Treatment Satisfaction Survey-Intraocular Pressure had the highest number of positive ratings in the content validity assessment.

CONCLUSION: This study provides a descriptive catalogue of vision-specific PRO instruments, to inform the choice of an appropriate measure of patient-reported outcomes in a glaucoma context.

Patient-reported outcomes in randomised controlled trials on age-related macular degeneration

BACKGROUND/AIMS: The purpose of this systematic review was to identify the frequency and type of patient-reported outcome measures (PROMs) used in recent randomised controlled trials (RCTs) for age-related macular degeneration (AMD).

METHODS: The authors conducted a systematic search between January 2010 and November 2013 in MEDLINE, EMBASE, Scopus, Cochrane Library (Central) and the clinical trials registries (http://www.controlled-trials.com and http://www.ClinicalTrials.gov) according to defined inclusion criteria (RCTs on AMD in English). Two independent reviewers evaluated studies for inclusion. One reviewer extracted data of included studies, and a second masked reviewer assessed 10% to confirm accuracy in data collection. Reference lists of included papers and appendices of relevant Cochrane systematic reviews were scanned to identify other relevant RCTs. Information collected on extracted outcomes was analysed using descriptive statistics.

RESULTS: Literature and registry search yielded 3816 abstracts of journal articles and 493 records from trial registries. A total of 177 RCTs were deemed to have met inclusion criteria. Of the 858 outcomes reported, 38 outcomes were identified as PROMs (4.4%). Of the 177 RCTs examined, PROMs were used in 25 trials (14.1%). The National Eye Institute Visual Function Questionnaire-25 was the most frequently used PROM instrument (64% of RCTs with PROMs included).

CONCLUSIONS: This review highlights that a small proportion of AMD RCTs included PROMs as outcome measures and that there was a variety in the instruments used.

Establishing a population-based patient-reported outcomes study (PROMs) using national cancer registries across two jurisdictions: The Prostate Cancer Treatment, your experience (PiCTure) study

Objective: To establish an international patient-reported outcomes (PROMs) study among prostate cancer survivors, up to 18 years postdiagnosis, in two countries with different healthcare systems and ethical frameworks. Design: A cross-sectional, postal survey of prostate cancer survivors sampled and recruited via two population-based cancer registries. Healthcare professionals (HCPs) evaluated patients for eligibility to participate. Questionnaires contained validated instruments to assess health-related quality of life and psychological well-being, including QLQ-C30, QLQPR-25, EQ-5D-5L, 21-question Depression, Anxiety and Stress Scale (DASS-21) and the Decisional Regret Scale. Setting: Republic of Ireland (RoI) and Northern Ireland (NI). Primary outcome measures: Registration completeness, predictors of eligibility and response, data missingness, unweighted and weighted PROMs. Results: Prostate cancer registration was 80% (95% CI 75% to 84%) and 91% (95% CI 89% to 93%) complete 2 years postdiagnosis in NI and RoI, respectively. Of 12 322 survivors sampled from registries, 53% (n=6559) were classified as eligible following HCP screening. In the multivariate analysis, significant predictors of eligibility were: being ≤59 years of age at diagnosis (p<0.001), short-term survivor (<5 years postdiagnosis; p<0.001) and from RoI (p<0.001). 3348 completed the questionnaire, yielding a 54% adjusted response rate. 13% of men or their families called the study freephone with queries for assistance with questionnaire completion or to talk about their experience. Significant predictors of response in multivariate analysis were: being ≤59 years at diagnosis (p<0.001) and from RoI (p=0.016). Mean number of missing questions in validated instruments ranged from 0.12 (SD 0.71; EQ-5D-5L) to 3.72 (SD 6.30; QLQ-PR25). Weighted and unweighted mean EQ-5D-5L, QLQ-C30 and QLQ-PR25 scores were similar, as were the weighted and unweighted prevalences of depression, anxiety and distress. Conclusions: It was feasible to perform PROMs studies across jurisdictions, using cancer registries as sampling frames; we amassed one of the largest, international, population-based data set of prostate cancer survivors. We highlight improvements which could inform future PROMs studies, including utilising general practitioners to assess eligibility and providing a freephone service.

Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

BACKGROUND: Patient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.

METHODS: The CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b-T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923.

FINDINGS: 2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4-64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months.

INTERPRETATION: The incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer.

FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

The impact of specialized oncology nursing on patient supportive care outcomes

Meeting the supportive care needs of cancer patients remains a challenge to cancer care systems around the world. Despite significant improvements in the organization of medical care of patients with cancer, numerous surveys of cancer populations demonstrate that significant proportions of patients fail to have their supportive care needs met. One possible solution is the introduction of a care coordinator role using oncology nursing to help ensure that patients' physical, psychological, and social support needs are addressed. Although having face validity, there is little empirical evidence on the effects of nurse-led supportive care coordinator roles on patient reported supportive care outcomes. In this article the authors present the results of a prospective longitudinal cohort study of 113 patients referred to a community-based specialist oncology nursing program. Using validated instruments they found significant improvements in patient-reported outcomes in key supportive care domains: unmet needs, quality of life, and continuity of care, as well as a shift in patterns of health resource utilization from acute care settings to the community over the course of the intervention. The results of this study are important in supporting the design and development of controlled trials to examine provider roles in the coordination of supportive cancer care. Copyright © Taylor & Francis Group, LLC.

Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study

BACKGROUND: Radium-223 dichloride (radium-223), a first-in-class α-emitting radiopharmaceutical, is recommended in both pre- and post-docetaxel settings in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases based on overall survival benefit demonstrated in the phase III ALSYMPCA study. ALSYMPCA included prospective measurements of health-related quality of life (QOL) using two validated instruments: the general EuroQoL 5D (EQ-5D) and the disease-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P).

PATIENTS AND METHODS: Analyses were conducted to determine treatment effects of radium-223 plus standard of care (SOC) versus placebo plus SOC on QOL using FACT-P and EQ-5D. Outcomes assessed were percentage of patients experiencing improvement, percentage of patients experiencing worsening, and mean QOL scores during the study.

RESULTS: Analyses were carried out on the intent-to-treat population of patients randomized to receive radium-223 (n = 614) or placebo (n = 307). The mean baseline EQ-5D utility and FACT-P total scores were similar between treatment groups. A significantly higher percentage of patients receiving radium-223 experienced meaningful improvement in EQ-5D utility score on treatment versus placebo {29.2% versus 18.5%, respectively; P = 0.004; odds ratio (OR) = 1.82 [95% confidence interval (CI) 1.21-2.74]}. Findings were similar for FACT-P total score [24.6% versus 16.1%, respectively; P = 0.020; OR = 1.70 (95% CI 1.08-2.65)]. A lower percentage of patients receiving radium-223 experienced meaningful worsening versus placebo measured by EQ-5D utility score and FACT-P total score. Prior docetaxel use and current bisphosphonate use did not affect these findings. Treatment was a significant predictor of EQ-5D utility score, with radium-223 associated with higher scores versus placebo (0.56 versus 0.50, respectively; P = 0.002). Findings were similar for FACT-P total score (99.08 versus 95.22, respectively; P = 0.004).

CONCLUSIONS: QOL data from ALSYMPCA demonstrated that improved survival with radium-223 is accompanied by significant QOL benefits, including a higher percentage of patients with meaningful QOL improvement and a slower decline in QOL over time in patients with CRPC.

A systematic review of quantitative studies reporting selected patient experienced outcomes, with a specific focus on gender differences in people with colorectal cancer

Men with colorectal cancer have a higher mortality rate than their female counterparts. Despite this, there is a limited understanding of the impact gender has on the experience of colorectal cancer.

Pre-validation methods for developing a patient reported outcome instrument

BACKGROUND: Measures that reflect patients' assessment of their health are of increasing importance as outcome measures in randomised controlled trials. The methodological approach used in the pre-validation development of new instruments (item generation, item reduction and question formatting) should be robust and transparent. The totality of the content of existing PRO instruments for a specific condition provides a valuable resource (pool of items) that can be utilised to develop new instruments. Such 'top down' approaches are common, but the explicit pre-validation methods are often poorly reported. This paper presents a systematic and generalisable 5-step pre-validation PRO instrument methodology.

METHODS: The method is illustrated using the example of the Aberdeen Glaucoma Questionnaire (AGQ). The five steps are: 1) Generation of a pool of items; 2) Item de-duplication (three phases); 3) Item reduction (two phases); 4) Assessment of the remaining items' content coverage against a pre-existing theoretical framework appropriate to the objectives of the instrument and the target population (e.g. ICF); and 5) qualitative exploration of the target populations' views of the new instrument and the items it contains.

RESULTS: The AGQ 'item pool' contained 725 items. Three de-duplication phases resulted in reduction of 91, 225 and 48 items respectively. The item reduction phases discarded 70 items and 208 items respectively. The draft AGQ contained 83 items with good content coverage. The qualitative exploration ('think aloud' study) resulted in removal of a further 15 items and refinement to the wording of others. The resultant draft AGQ contained 68 items.

CONCLUSIONS: This study presents a novel methodology for developing a PRO instrument, based on three sources: literature reporting what is important to patient; theoretically coherent framework; and patients' experience of completing the instrument. By systematically accounting for all items dropped after the item generation phase, our method ensures that the AGQ is developed in a transparent, replicable manner and is fit for validation. We recommend this method to enhance the likelihood that new PRO instruments will be appropriate to the research context in which they are used, acceptable to research participants and likely to generate valid data.

Patient-reported 'ever had' and 'current' long term physical symptoms following prostate cancer treatments

OBJECTIVE: To document prostate cancer patient reported 'ever experienced' and 'current' prevalence of disease specific physical symptoms stratified by primary treatment received.
PATIENTS: 3,348 prostate cancer survivors 2-15 years post diagnosis.
METHODS: Cross-sectional, postal survey of 6,559 survivors diagnosed 2-15 years ago with primary, invasive PCa (ICD10-C61) identified via national, population based cancer registries in Northern Ireland and Republic of Ireland. Questions included symptoms at diagnosis, primary treatments and physical symptoms (impotence/urinary incontinence/bowel problems/breast changes/loss of libido/hot flashes/fatigue) experienced 'ever' and at questionnaire completion ("current"). Symptom proportions were weighted by age, country and time since diagnosis. Bonferroni corrections were applied for multiple comparisons.
RESULTS: Adjusted response rate 54%; 75% reported at least one 'current' physical symptom ('ever':90%), with 29% reporting at least three. Prevalence varied by treatment; overall 57% reported current impotence; this was highest following radical prostatectomy (RP)76% followed by external beam radiotherapy with concurrent hormone therapy (HT); 64%. Urinary incontinence (overall 'current' 16%) was highest following RP ('current'28%, 'ever'70%). While 42% of brachytherapy patients reported no 'current' symptoms; 43% reported 'current' impotence and 8% 'current' incontinence. 'Current' hot flashes (41%), breast changes (18%) and fatigue (28%) were reported more often by patients on HT.
CONCLUSION: Symptoms following prostate cancer are common, often multiple, persist long-term and vary by treatment. They represent a significant health burden. An estimated 1.6% of men over 45 is a prostate cancer survivor currently experiencing an adverse physical symptom. Recognition and treatment of physical symptoms should be prioritised in patient follow-up. This information should facilitate men and clinicians when deciding about treatment as differences in survival between radical treatments is minimal.

Systematic evaluation of patient-reported outcome (PRO) protocol content and reporting in UK cancer clinical trials: the EPiC study protocol

Introduction Emerging evidence suggests that patient-reported outcome (PRO)-specific information may be omitted in trial protocols and that PRO results are poorly reported, limiting the use of PRO data to inform cancer care. This study aims to evaluate the standards of PRO-specific content in UK cancer trial protocols and their arising publications and to highlight examples of best-practice PRO protocol content and reporting where they occur. The objective of this study is to determine if these early findings are generalisable to UK cancer trials, and if so, how best we can bring about future improvements in clinical trials methodology to enhance the way PROs are assessed, managed and reported. Hypothesis: Trials in which the primary end point is based on a PRO will have more complete PRO protocol and publication components than trials in which PROs are secondary end points.

Methods and analysis Completed National Institute for Health Research (NIHR) Portfolio Cancer clinical trials (all cancer specialities/age-groups) will be included if they contain a primary/secondary PRO end point. The NIHR portfolio includes cancer trials, supported by a range of funders, adjudged as high-quality clinical research studies. The sample will be drawn from studies completed between 31 December 2000 and 1 March 2014 (n=1141) to allow sufficient time for completion of the final trial report and publication. Two reviewers will then review the protocols and arising publications of included trials to: (1) determine the completeness of their PRO-specific protocol content; (2) determine the proportion and completeness of PRO reporting in UK Cancer trials and (3) model factors associated with PRO protocol and reporting completeness and with PRO reporting proportion.

Ethics and dissemination The study was approved by the ethics committee at University of Birmingham (ERN_15-0311). Trial findings will be disseminated via presentations at local, national and international conferences, peer-reviewed journals and social media including the CPROR twitter account and UOB departmental website (http://www.birmingham.ac.uk/cpro0r).

The effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle-closure glaucoma (EAGLE): Study protocol for a randomized controlled trial

BACKGROUND: Glaucoma is the leading cause of irreversible blindness. Although primary open-angle glaucoma is more common, primary angle-closure glaucoma (PACG) is more likely to result in irreversible blindness. By 2020, 5·3 million people worldwide will be blind because of PACG. The current standard care for PACG is a stepped approach of a combination of laser iridotomy surgery (to open the drainage angle) and medical treatment (to reduce intraocular pressure). If these treatments fail, glaucoma surgery (eg, trabeculectomy) is indicated. It has been proposed that, because the lens of the eye plays a major role in the mechanisms leading to PACG, early clear lens extraction will improve glaucoma control by opening the drainage angle. This procedure might reduce the need for drugs and glaucoma surgery, maintain good visual acuity, and improve quality of life compared with standard care.EAGLE aims to evaluate whether early lens extraction improves patient-reported, clinical outcomes, and cost-effectiveness, compared with standard care.

METHODS/DESIGN: EAGLE is a multicentre pragmatic randomized trial. All people presenting to the recruitment centres in the UK and east Asia with newly diagnosed PACG and who are at least 50 years old are eligible.The primary outcomes are EQ-5D, intraocular pressure, and incremental cost per quality adjusted life year (QALY) gained. Other outcomes are: vision and glaucoma-specific patient-reported outcomes, visual acuity, visual field, angle closure, number of medications, additional surgery (e.g., trabeculectomy), costs to the health services and patients, and adverse events.A single main analysis will be done at the end of the trial, after three years of follow-up. The analysis will be based on all participants as randomized (intention to treat). 400 participants (200 in each group) will be recruited, to have 90% power at 5% significance level to detect a difference in EQ-5D score between the two groups of 0·05, and a mean difference in intraocular pressure of 1·75 mm Hg. The study will have 80% power to detect a difference of 15% in the glaucoma surgery rate.

TRIAL REGISTRATION: ISRCTN44464607.

The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis

BACKGROUND: Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

RESULTS: Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

CONCLUSIONS: Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).