Primary Health-related Quality Of Life Endpoints Research Articles

Health-related quality of life and quality-adjusted progression free survival for carfilzomib and dexamethasone maintenance following salvage autologous stem-cell transplantation in patients with multiple myeloma: a randomized phase 2 trial by the Nordic Myeloma Study Group

BackgroundDecisions regarding maintenance therapy in patients with multiple myeloma should be based on both treatment efficacy and health-related quality of life (HRQL) consequences. In the CARFI trial, patients with first relapse of multiple myeloma underwent salvage autologous stem cell transplantation (salvage ASCT) before randomization to carfilzomib-dexamethasone maintenance therapy (Kd) or observation. The primary clinical endpoint was time to progression, which was extended by 8 months by Kd. The aim of this paper is to present the all HRQL endpoints of the CARFI trial including the HRQL effect of Kd maintenance therapy relative to observation. The primary HRQL endpoint was assessed by EORTC QLQ-C30 Summary score (QLQ-C30-sum) at 8 months follow-up. A key secondary HRQL endpoint was quality-adjusted progression-free-survival (QAPFS).MethodsHRQL was assessed with EORTC QLQ-C30, EORTC QLQ-MY20 and FACT/GOG-Ntx at randomization and every second month during follow-up. HRQL data were analyzed with linear mixed effect models until 8 months follow-up. QAPFS per individual was calculated by multiplying progression-free survival (PFS) by two quality-adjustment metrics, the QLQ-C30-sum and EORTC Quality of Life Utility Measure-Core 10 dimensions (QLU-C10D). The QAPFS per treatment group was estimated with the Kaplan-Meier method. P < 0.05 was used for statistical significance, and a between-group minimal important difference of 10 points was interpreted as clinically relevant for the QLQ-C30-sum.Results168 patients were randomized. HRQL questionnaire compliance was 93%. For the QLQ-C30-sum, the difference of 4.62 points (95% confidence interval (CI) -8.9: -0.4, p = 0.032) was not clinically relevant. PFS was 19.3 months for the Kd maintenance group and 16.8 months for the observation group; difference = 2.5 months (95% CI 0.5; 4.5). QAPFS based on the QLQ-C30-sum for the Kd maintenance group was 18.0 months (95% CI 16.4; 19.6) and for the observation group 15.0 months (95% CI 13.5; 16.5); difference = 3.0 months (95% CI 0.8–5.3). QAPFS based on the QLU-C10D for the Kd maintenance group was 17.5 months (95% CI 15.9; 19.2) and 14.0 months (95% CI 12.4; 15.5) for the observation group; difference = 3.5 months (95% CI 1.1–5.9).ConclusionsKd maintenance therapy after salvage ASCT did not adversely affect overall HRQL, but adjustment for HRQL reduced the PFS compared to unadjusted PFS. PFS of maintenance therapy should be quality-adjusted to balance the benefits and HRQL impact.

10-Day Decitabine Versus Intensive Chemotherapy Followed By Transplantation in Fit AML Patients Aged ≥60 Years: Health-Related Quality of Life Outcomes of the Randomized Phase III Trial AML21 of the EORTC Leukemia Group, Gimema, Celg, and Gmds-SG

Background To assess the optimal treatment strategy for fit older patients with acute myeloid leukemia (AML), we performed a large international phase III randomized controlled trial (RCT) in fit AML patients aged >60 years, comparing 10-day decitabine (DEC) followed by allografting (HSCT) versus intensive chemotherapy (IC, "3+7" regimen) followed by HSCT. This trial revealed comparable HSCT rates and survival outcomes, but a more favorable safety profile with DEC when compared to IC (Lübbert M. et al, HemaSphere, 6, 26-27, 2022), supporting the hypothesis that reduced toxicity translates into a better health-related quality of life (HRQoL). Objective We hereby report the HRQoL outcomes of this international RCT. Patients and Methods HRQoL was a secondary endpoint and was assessed by the EORTC QLQ-C30 and its validated module for evaluating HRQoL in older patients, namely the EORTC QLQ-ELD14. Key inclusion criteria were: newly diagnosed AML, age >60 years, eligibility for IC, and a WHO performance status of ≤2. Assessments of HRQoL were performed at baseline and then at 2 (at regeneration after two treatment cycles), 6 and 12 months. For patients undergoing a HSCT, HRQoL was assessed prior to the procedure and at day 100 after the transplant. Quality of life deterioration (QD) was defined as any of the following events: death, progression, and clinically meaningful deterioration from baseline in at least one of the five pre-selected primary HRQoL scales (i.e., physical functioning, role functioning, fatigue, pain, and illness burden). The two co-primary endpoints were: QD at 2 months and QD at 6 or 12 months. A difference of 10 points or more was considered clinically meaningful. We hypothesized better HRQoL outcomes for patients treated with DEC. The changes in the primary HRQoL scales from baseline to 2 months and from baseline to the average of 6 and 12 months were secondary HRQoL endpoints. HRQoL trajectories of patients undergoing HSCT on-study based on evaluations at baseline, prior to HSCT and at day 100 after HSCT were also described. This study was registered at ClinicalTrials.gov (NCT02172872). Results Between December 2014 and August 2019, 606 patients were randomized and a baseline HRQoL assessment was available for 549 patients (91%): 279 out of 303 in the DEC arm and 270 out of 303 in the IC arm. Compliance among alive patients at 2, 6 and 12 months was 57%, 57%, and 64%, respectively. The proportion of patients evaluable for QD at 2 months was 60%. The proportion of patients evaluable for QD at 6 or 12 months was 82%. Analysis of the primary HRQoL endpoint showed that the proportion of patients deteriorating at 2 months was 76% (95% CI, 69 to 82%) in the DEC group vs 88% (95% CI, 82 to 93%) in the IC group (odds ratio 0.43 [95% CI, 0.24 to 0.76], P=.003). Several sensitivity analyses, using multiple imputation to deal with missing values and predefined modifications of the definition of QD, confirmed this finding. QD analysis at 6 or 12 months indicated no statistically significant difference between both arms (odds ratio 0.83 [95% CI, 0.46 to 1.52]). At 2 months from randomization, the illness burden scale increased by 4.19 (95% CI, -0.44 to 8.83) points in the DEC and by 15.15 (95% CI, 9.88 to 20.42) points in the IC arm, indicating a clinically meaningful and statistically significant difference of -10.96 (95% CI, -17.94 to -3.97), P=.004. The changes in the primary HRQoL scales from baseline to 2 months and from baseline to the average of 6 and 12 months are presented in Table 1. Baseline data were available for 218 of the 240 patients who received an on-study HSCT. Clinically meaningful HRQoL deteriorations between baseline and post-HSCT in the IC group were observed in all primary HRQoL scales except for pain. The change from baseline to post-HSCT HRQoL in the DEC arm appeared less pronounced and did not reach the threshold of clinical relevance. Conclusions Following two months of treatment, there was a significantly lower percentage of patients treated with DEC who reported HRQoL deterioration, compared to those treated with IC. Additionally, patients treated with DEC did not experience any clinically meaningful deterioration in key pre-specified HRQoL domains post-HSCT, while this was the case for patients treated with IC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patient-reported health-related quality of life from a randomized phase II trial comparing standard-dose with high-dose twice daily thoracic radiotherapy in limited stage small-cell lung cancer

ObjectivesIn a randomized phase II trial, twice daily (BID) thoracic radiotherapy (TRT) of 60 Gy/40 fractions improved survival compared with 45 Gy/30 fractions in limited stage small-cell lung cancer (LS SCLC). Notably, the higher dose did not cause more toxicity. Here we present health related quality of life (HRQoL) reported by the trial participants during the first 2 years. Materials and methods170 patients were randomized 1:1 to TRT of 45 Gy or 60 Gy concurrently with cisplatin/etoposide chemotherapy. The 150 patients who commenced TRT and completed a minimum of one HRQoL-questionnaire were included in the present study. Patients reported HRQoL on the European Organization for Research and Treatment of Cancer Core 30 and Lung Cancer 13 Quality of Life Questionnaires. Questionnaires were completed weeks 0, 4 (before TRT), 8 (end of TRT), 12 (response evaluation after chemoradiotherapy) and 16 (end of prophylactic cranial irradiation), then every 10 weeks year one, and every 3 months year two. Primary HRQoL endpoints were dysphagia and dyspnea. A difference in mean score of ≥10 was defined as clinically significant. ResultsMaximum dysphagia was reported on week 8, with no significant difference between treatment arms (mean scores 45 Gy: 44.2, 60 Gy: 51.1). The 60 Gy arm had more dysphagia in the convalescence period, but dysphagia scores returned to baseline levels at week 16 in both arms. For dyspnea there were no significant changes, or differences between treatment arms, at any timepoint. There were no significant differences between treatment arms for any other HRQoL-scales. ConclusionTRT of 60 Gy did not cause significantly higher maximum dysphagia, though patients on the 60 Gy arm reported more dysphagia the first 8 weeks of convalescence. The higher dose was well tolerated and is an attractive alternative to current TRT schedules in LS SCLC.Trial reg Clinicaltrials.gov NCT0204184.

Patient-centred outcomes and effect of disease progression on health status in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation receiving maintenance olaparib or placebo (SOLO1): a randomised, phase 3 trial

In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status. SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0-1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy-Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986. Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9-42·9) for olaparib and 41·2 months (32·2-41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI -0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of -3·00, 95% CI -4·78 to -1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20-31·63] vs placebo 17·58 [15·05-20·18]; difference 12·17 months [95% CI 9·07-15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82-35·49] vs placebo 20·24 months [17·36-23·11]; difference 12·92 months [95% CI 9·30-16·54]; p<0·0001) were significantly longer with olaparib than with placebo. The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo. AstraZeneca and Merck Sharp & Dohme.

Improving quality of health-related quality of life (HRQOL) reporting in phase III randomized controlled trials (RCTs) of metastatic prostate cancer (mPC).

58 Background: HRQOL data are increasingly used to guide patient care and health policy. However, their utility can be compromised by inadequate quality of HRQOL reporting (QHR). We aimed to evaluate QHR in phase III RCTs of mPC. Methods: A systematic review following PRISMA guidelines identified published manuscripts of phase III RCTs of mPC assessing systemic therapies (excluding androgen deprivation therapy and bone targeting agents) between 1990 - 2019. Supplements, references and companion publications were reviewed. QHR was independently quantified using the Minimum Standard Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials (MSC, range 0-11) by 2 investigators. QHR is “probably robust” if MSC score is ≥8 and all 3 mandatory items (baseline compliance, missing data, and psychometric properties) are reported; “limited” if score is 5-7; and “very limited” if score is ≤4. Results: HRQOL was the primary (11%), secondary (61%), explorative (21%), and unspecified (7%) endpoint in 57/76 (75%) RCTs, and reported in 46/57 (81%). Primary HRQOL endpoints were pain palliation only. MSC scores ranged 2 – 11. QHR was mostly limited (Table). Most RCTs did not report mode of administration (82%), rationale for selected instrument (65%), or missing data (59%). Other common limitations were: unreported baseline compliance (35%), lack of culturally validated measure (33%), clinical significance not discussed (33%), no hypotheses stated (28%), and inadequate coverage of HRQOL domains (26%). QHR has improved since 2015, with the median MSC score reaching 8 (Table). Conclusions: QHR has improved considerably over time, with many recent phase III RCTs in mPC reporting “probably robust” HRQOL data. Within existing resource constraints however, nonreporting and methodologic deficiencies still remain. The use of standard checklists may further enhance QHR and promote high quality HRQOL research.[Table: see text]

P12 LONG-TERM QUALITY OF LIFE AFTER TOTAL GASTRECTOMY VERSUS IVOR LEWIS ESOPHAGECTOMY

Abstract Aim The aim of this study was to investigate the difference in long-term health-related quality of life in patients undergoing total gastrectomy versus Ivor Lewis esophagectomy in a tertiary referral center. Background &amp; Methods Surgical treatment for gastroesophageal junction (GEJ) cancers is challenging. Both a total gastrectomy and an esophagectomy can be performed. Which of the two should be preferred is unknown given the scarce evidence regarding effects on surgical morbidity, pathology, long-term survival and health-related quality of life (HR-QoL). From 2014 to 2018, patients with a follow-up of &gt; 1 year after either a total gastrectomy or an Ivor Lewis esophagectomy for GEJ or cardia carcinoma completed the EORTC QLQ-C30 and EORTC QLQ-OG25 questionnaires. Problems with eating, reflux and nausea and vomiting were chosen as the primary HR-QoL endpoints. The secondary endpoints were the remaining HR-QoL domains, postoperative complications and pathology results. Multivariable linear regression was applied taking confounders age, gender, ASA classification and neoadjuvant therapy into account. Results 30 patients after gastrectomy and 71 after Ivor Lewis esophagectomy with a mean age of 63 years were included. Median follow-up was two years (range 12-84 months). Patients after total gastrectomy reported significantly less choking when swallowing and coughing (β=-5.952, 95% CI -9.437 – -2.466; β=-13.084, 95% CI -18.525 – -7.643). Problems with eating, reflux and nausea and vomiting were not significantly different between the two groups. No significant difference was found in postoperative complications or Clavien-Dindo grade. Significantly more lymph nodes were resected in esophagectomy group (p=0.008). No difference in number of positive lymph nodes or R0 resection was found. Conclusion After a follow-up of &gt; 1 year choking when swallowing and coughing were less common after total gastrectomy. No significant difference was found in problems with eating, reflux or nausea and vomiting nor in postoperative complications or radicality of surgery. Based on this study no general preference can be given to either of the procedures for GEJ cancer. Patients may be informed about the HR-QoL domains that are likely to be affected by the different surgical procedures, which in turn may support shared decision making when a choice between the two treatment options is possible.

Long-Term Quality of Life After Total Gastrectomy Versus Ivor Lewis Esophagectomy

BackgroundThere is scarce evidence on whether a total gastrectomy or an Ivor Lewis esophagectomy is preferred for gastroesophageal junction (GEJ) cancers regarding effects on morbidity, pathology, survival and health-related quality of life (HR-QoL). The aim of this study was to investigate the difference in long-term HR-QoL in patients undergoing total gastrectomy versus Ivor Lewis esophagectomy in a tertiary referral center.MethodsPatients with a follow-up of >1 year after a total gastrectomy or an Ivor Lewis esophagectomy for GEJ/cardia carcinoma completed the EORTC QLQ-C30 and EORTC QLQ-OG25 questionnaires. ‘Problems with eating,’ ‘reflux,’ and ‘nausea and vomiting’ were the primary HR-QoL endpoints. The secondary endpoints were the remaining HR-QoL domains, postoperative complications and pathology results.ResultsThirty patients after gastrectomy and 71 after esophagectomy were included. Mean age was 63 years. Median follow-up was 2 years (range 12–84 months). Patients after gastrectomy reported less ‘choking when swallowing’ and ‘coughing’ (β = − 5.952, 95% CI − 9.437 to − 2.466; β = − 13.084, 95% CI − 18.525 to − 7.643). More lymph nodes were resected in esophagectomy group (p = 0.008). No difference was found in number of positive lymph nodes, R0 resection or postoperative complications.ConclusionsAfter a follow-up of >1 year ‘choking when swallowing’ and ‘coughing’ were less common after a total gastrectomy. No differences were found in postoperative complications or radicality of surgery. Based on this study, no general preference can be given to either of the procedures for GEJ cancer. These results support shared decision making when a choice between the two treatment options is possible.

Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial

BackgroundThe phase III OlympiAD study (NCT02000622) showed a statistically significant progression-free survival benefit with olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA mutation and human epidermal growth factor receptor 2-negative metastatic breast cancer. From this study, we report the effect of olaparib on health-related quality of life (HRQoL). MethodsPatients were randomised 2:1 to olaparib monotherapy (300 mg twice daily) or single-agent TPC. The primary HRQoL end-point was mean change from baseline in the two-item global health status/QoL score determined from patient-completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module (EORTC QLQ-C30) questionnaires and assessed using a mixed model for repeated measures. Symptoms and functioning domains, best overall response and time to deterioration of QoL were also evaluated. ResultsOverall questionnaire compliance rates were 93.2% for olaparib and 76.3% for TPC. Between-treatment global health status/QoL comparison showed a significant improvement in the olaparib arm versus the TPC arm, with mean change of 3.9 (standard deviation 1.2) versus −3.6 (2.2), a difference of 7.5 points (95% confidence interval [CI]: 2.48, 12.44; P = 0.0035). A higher proportion of patients in the olaparib arm showed a best overall response of ‘improvement’ in global health status/QoL (33.7% vs 13.4%). Median time to global health status/QoL deterioration was not reached in olaparib patients and was 15.3 months for TPC patients (hazard ratio: 0.44 [95% CI: 0.25, 0.77]; P = 0.004). For EORTC QLQ-C30 symptoms and functioning subscales, only nausea/vomiting symptom score was worse in the olaparib arm than in the TPC arm (across all visits compared with baseline). ConclusionHRQoL was consistently improved for patients treated with olaparib, compared with chemotherapy TPC.

Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials

Background: Many patients experience toxicity from chemotherapy that may negatively impact their health-related quality of life (HRQoL), but side effects often go undetected by health care personnel. Our aim was to investigate whether hematologic toxicity (HT) was associated with HRQoL impairment, and, consequently, if blood counts could be used to identify patients with the highest need for supportive care during chemotherapy.Material and methods: Data from two phase III trials of first-line chemotherapy in advanced non-small-cell lung cancer (NSCLC) were analyzed (n = 873). Blood counts were measured weekly in the treatment period. We categorized patients as having severe (CTCAE grade 3–4) or non-severe (grade 0–2) HT during the first chemotherapy cycle. HRQoL was reported on the EORTC QLQ-C30 and LC13 before and at the end of the cycle. The primary endpoints were changes in global quality of life, fatigue, nausea/vomiting and dyspnea (LC13).Results: Of the 766 patients with complete data set, 177 (23%) developed severe HT during the first chemotherapy cycle. Changes in fatigue and nausea/vomiting were significantly worse for patients experiencing severe compared to patients with non-severe HT (difference in mean change of 4.9 points; p = .01, and 6.4 points; p = .01, respectively), but this association was limited to neutropenia, not thrombocytopenia or anemia. There were no significant associations between HT and global quality of life or dyspnea (difference in mean change of 2.1 points; p = .28, and 3.3 points; p = .053, respectively).Conclusions: Patients developing severe HT had worse changes in two out of four of the primary HRQoL endpoints, but the association was not strong enough to use blood counts to identify patients who need more clinical attention and supportive care during chemotherapy.

Health-related quality of life in patients with chronic myeloid leukemia receiving first-line therapy with nilotinib.

Although a wealth of efficacy and safety data is available for many tyrosine kinase inhibitors used in chronic myeloid leukemia (CML), there is a dearth of information on their impact on patients' health-related quality of life (HRQOL). The primary objective of this study was to evaluate HRQOL and fatigue outcomes in patients with CML receiving first-line therapy with nilotinib. This was a multicenter, prospective study enrolling 130 patients with chronic-phase CML. HRQOL and fatigue were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and its validated Fatigue module at the baseline and then at 3, 6, 12, 18, and 24 months. The primary prespecified HRQOL endpoints defined in the study protocol for longitudinal analysis were the Physical Functioning, Social Functioning, Role Functioning, and Fatigue scales. The remaining scales were investigated on an exploratory basis. The rate of baseline compliance with the HRQOL assessment was 95.4% (124 of 130), and the rate of overall compliance with HRQOL forms was 91%. Among the 4 prespecified primary HRQOL endpoints, statistically significant improvements over time were found for Physical Functioning (P = .013), Role Functioning (P = .004), and Fatigue (P < .001). Clinically meaningful improvements were found already 3 months after the treatment start. The baseline patient self-reported fatigue severity was an independent predictive factor for the achievement of a major molecular response with an odds ratio of 0.960 (95% confidence interval, 0.934-0.988; P = .005). For most patients, HRQOL improvements with nilotinib occur during the early phase of therapy and are maintained over time. Also, a more systematic HRQOL evaluation during the diagnostic workup of CML may help to predict clinical outcomes. Cancer 2018;124:2228-37. © 2018 American Cancer Society.

Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial

The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial. EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]). Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events. Bristol-Myers Squibb.

Health-related quality of life (HRQoL) results from the AURELIA trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum-resistant recurrent ovarian cancer (OC).

5542 Background: Adding BEV to CT significantly improved PFS in platinum-resistant OC in the open-label phase III AURELIA trial. As symptom improvement is a major goal of treatment, determining effects on HRQoL was a key secondary aim of AURELIA. Methods: After investigator selection of single-agent CT (pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel), patients (pts) with measurable/assessable platinum-resistant OC were randomized to CT ± BEV. HRQoL and symptoms were assessed at baseline and every 2 or 3 cycles (8/9 wks) until PD using the EORTC OC Module (OV28) and FOSI. The primary HRQoL endpoint was an absolute improvement of ≥15% (≥15 points) on the 100-point OV28 subscale for abdominal (abdo)/GI symptoms (items 1–6) at wk 8/9. Pts with missing questionnaires (Qs) were included and considered not to have improved. A sensitivity analysis excluded pts with Qs missing for reasons other than PD/death or switch from CT to BEV. Subgroup analyses of symptomatic pts included only those with a baseline score ≥15 (sufficient to show ≥15-point improvement). Mixed-model repeated measures (MMRM) analysis was used to compare Qs from all time points until PD/death, not just wk 8/9. The FOSI was analyzed similarly. Results: Baseline Qs were available from 89% of 361 randomized pts. At wk 8/9, 81% of BEV–CT vs 68% of CT pts who were alive and PD-free returned OV28 Qs. For the primary HRQoL endpoint, more BEV–CT than CT pts had a ≥15% improvement in the OV28 abdo/GI symptom subscale at wk 8/9 (21.9% vs 9.3%, 12.7% difference [95% CI 4.4–20.9]; p = 0.002). The sensitivity analysis described above showed a 13.3% difference [95% CI 4.5–22.1]. In the subgroup of 233 pts with a baseline score ≥15, there was a 16.9% difference (95% CI 6.1–27.6) favoring BEV–CT (29.6% vs 12.7%). MMRM analysis of OV28 abdo/GI symptom subscale scores also favored BEV–CT (6.4-point difference [95% CI 1.28–11.6]). More BEV–CT than CT pts had a ≥15% improvement in FOSI score at wk 8/9 (12.2% vs 3.1%, 9.0% difference [95% CI 2.9–15.2]). Conclusions: Adding BEV to CT resulted in more frequent ≥15% improvements in patient-reported abdo/GI symptoms in platinum-resistant OC. Clinical trial information: NCT00976911.

Health-related quality of life outcomes of docetaxel/carboplatin combination therapy vs. sequential therapy with docetaxel then carboplatin in patients with relapsed, platinum-sensitive ovarian cancer: Results from a randomized clinical trial

Objectives A phase II clinical trial compared docetaxel in combination with carboplatin to sequential single agent docetaxel followed by carboplatin for treatment of recurrent platinum-sensitive ovarian, peritoneal, or tubal cancer. This manuscript reports prospectively collected health-related quality of life (HRQL). Methods Participants were randomized to either weekly docetaxel 30 mg/m 2/days 1 and 8 and carboplatin AUC 6/day 1 every 3 weeks (cDC) or docetaxel 30 mg/m 2/days 1 and 8, repeated every 3 weeks for 6 cycles followed by carboplatin AUC 6/day 1 every 3 weeks for 6 cycles or until disease progression (sDC). The primary HRQL endpoint was the trial outcome index (TOI) score of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) instrument, and was assessed as an intent-to-treat analysis. The secondary HRQL endpoints included the FACT-O total score, the FACT-General, and several domain scores of the FACT-O instrument (physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and the ovarian cancer specific (OCS) module). The FACT-O was administered at randomization, prior to each of 6 cycles of treatment, and at study endpoint. Results One hundred forty-eight participants were randomized to each group. Sequential docetaxel followed by carboplatin (sDC) was associated with significant improvements in the FACT-O TOI (p = 0.013), FACT-O total score (p = 0.033), and OCS (p = 0.029) compared to the combination docetaxel and carboplatin group (cDC). Conclusions Sequential single agent docetaxel followed by carboplatin is associated with improved HRQL when compared to cDC. The improved progression-free survival observed with cDC should be weighed against lower quality of life during treatment.

Quality-of-life results of an EORTC phase III randomized trial of adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases of solid tumors.

9036 Background: This study aimed to evaluate the effects of adjuvant whole brain radiotherapy (WBR) compared to no further radiotherapy after local treatment of a limited number of brain metastases in patients with stable solid tumor. We present the Health Related Quality of Life (HRQOL) results. Methods: HRQOL (EORTC QOL-C30 and BN-20) was a secondary endpoint in the trial. Out of 359, 317 patients (88.3% compliance) had baseline HRQOL assessments. Compliance was a challenge in this population: at month 6 some 51% of patients completed a HRQOL measure and at year one 45.1%. Therefore the analysis focuses on only the first year post baseline. The primary HRQOL endpoint was global QoL; secondary HRQOL endpoints were Cognitive, Physical, Emotional, Role Functioning and Fatigue. Sensitivity analyses were planned and undertaken for all scales. Statistical significance required p≤0.05 and clinical relevance ≥10 pt difference. Results: Over the year studied, there were no significant differences in the primary endpoint, global HRQOL (p<0.12). Patients who underwent WBR had a lower physical functioning score (p = 0.0325) and a deteriorated cognitive function (p = 0.006). However, the difference in physical function was clinically relevant only at week 8 and that in cognitive function only at year one. No differences between the treatments were found for role (p>0.1) or emotional functioning (p>0.1) or fatigue (p = 0.077). Exploratory analysis of several other HRQOL scales suggested worse scores for the WBR group, but these differences were not clinically relevant (<10 pt) and were not sustained in time for most other scales. Explorations also suggested that the detriment was generally greater in patients who had WBRT after radio surgery than after surgical removal of the brain metastases. Conclusions: In summary, patients who underwent WBR suffered from worse HRQOL levels, but very few differences were observed or reached the level of clinical or statistical significance. No significant financial relationships to disclose.

Phase III Study by the Norwegian Lung Cancer Study Group: Pemetrexed Plus Carboplatin Compared With Gemcitabine Plus Carboplatin As First-Line Chemotherapy in Advanced Non–Small-Cell Lung Cancer

PURPOSE To compare pemetrexed/carboplatin with a standard regimen as first-line therapy in advanced non-small-cell lung cancer NSCLC. PATIENTS AND METHODS Patients with stage IIIB or IV NSCLC and performance status of 0 to 2 were randomly assigned to receive pemetrexed 500 mg/m(2) plus carboplatin area under the curve (AUC) = 5 (Calvert's formula) on day 1 or gemcitabine 1,000 mg/m(2) on days 1 and 8 plus carboplatin AUC = 5 on day 1 every 3 weeks for up to four cycles. The primary end point was health-related quality of life (HRQoL) defined as global quality of life, nausea/vomiting, dyspnea, and fatigue reported on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and the lung cancer-specific module LC13 during the first 20 weeks. Secondary end points were overall survival and toxicity. Results Four hundred thirty-six eligible patients were enrolled from April 2005 to July 2006. Patients who completed the baseline questionnaire were analyzed for HRQoL (n = 427), and those who received > or = one cycle of chemotherapy were analyzed for toxicity (n = 423). Compliance of HRQoL questionnaires was 87%. There were no significant differences for the primary HRQoL end points or in overall survival between the two treatment arms (pemetrexed/carboplatin, 7.3 months; gemcitabine/carboplatin, 7.0 months; P = .63). The patients who received gemcitabine/carboplatin had more grade 3 to 4 hematologic toxicity than patients who received pemetrexed/carboplatin, including leukopenia (46% v 23%, respectively; P < .001), neutropenia (51% v 40%, respectively; P = .024), and thrombocytopenia (56% v 24%, respectively; P < .001). More patients on the gemcitabine/carboplatin arm received transfusions of RBCs and platelets, whereas the frequencies of neutropenic infections and thrombocytopenic bleedings were similar on both arms. CONCLUSION Pemetrexed/carboplatin provides similar HRQoL and survival when compared with gemcitabine/carboplatin with less hematologic toxicity and less need for supportive care.

Prophylactic Cranial Irradiation in Extensive Disease Small-Cell Lung Cancer: Short-Term Health-Related Quality of Life and Patient Reported Symptoms—Results of an International Phase III Randomized Controlled Trial by the EORTC Radiation Oncology and Lung Cancer Groups

Prophylactic cranial irradiation (PCI) in patients with extensive-disease small-cell lung cancer (ED-SCLC) leads to significantly fewer symptomatic brain metastases and improved survival. Detailed effects of PCI on health-related quality of life (HRQOL) are reported here. Patients (age, 18 to 75 years; WHO < or = 2) with ED-SCLC, and any response to chemotherapy, were randomly assigned to either observation or PCI. Health-related quality of life (HRQOL) and patient-reported symptoms were secondary end points. The European Organisation for the Research and Treatment of Cancer core HRQOL tool (Quality of Life Questionnaire C30) and brain module (Quality of Life Questionnaire Brain Cancer Module) were used to collect self-reported patient data. Six HRQOL scales were selected as primary HRQOL end points: global health status; hair loss; fatigue; and role, cognitive and emotional functioning. Assessments were performed at random assignment, 6 weeks, 3 months, and then 3-monthly up to 1 year and 6-monthly thereafter. Compliance with the HRQOL assessment was 93.7% at baseline and dropped to 60% at 6 weeks. Short-term results up to 3 months showed that there was a negative impact of PCI on selected HRQOL scales. The largest mean difference between the two arms was observed for fatigue and hair loss. The impact of PCI on global health status as well as on functioning scores was more limited. For global health status, the observed mean difference was eight points on a scale 0 to 100 at 6 weeks (P = .018) and 3 months (P = .055). PCI should be offered to all responding ED SCLC patients. Patients should be informed of the potential adverse effects from PCI. Clinicians should be alert to these; monitor their patients; and offer appropriate support, clinical, and psychosocial care.

Health-related quality of life of patients with overactive bladder receiving immediate-release tolterodine

Overactive bladder (OAB) imposes a burden on many aspects of a patient's life. The health-related quality of life (HRQOL) of OAB patients has been shown to be lower than healthy or control patients. A goal of successful treatment is to improve the HRQOL of OAB patients. With newer OAB treatments becoming available, HRQOL is an important outcome to measure. Thus, the objective of this study was to compare the HRQOL of patients being treated with tolterodine immediate-release (IR) versus placebo for OAB. The King's Health Questionnaire (KHQ) and the Medical Outcomes Study Short Form 36 (SF-36) were administered at baseline and end of treatment (12 weeks) in a randomized, parallel groups, placebo-controlled, double-blind, multinational study designed to compare the clinical efficacy and safety of tolterodine to placebo in the treatment of OAB. At end of treatment KHQ domains selected a priori as primary HRQOL endpoints (incontinence impact and role limitations) significantly improved (P≤0.0001) with tolterodine IR. Domains selected a priori as secondary HRQOL or symptom endpoints (physical limitations, emotions, sleep and energy, severity (coping) measures, and symptom severity) were also significantly improved (P≤0.0074) following treatment with tolterodine IR. The tolterodine IR group had less severity of individual symptoms and significantly better patient rating of bladder control than the placebo group at end of treatment. As expected, the SF-36 did not detect treatment differences. In conclusion, many aspects of HRQOL, as measured by the KHQ, significantly improved with tolterodine IR treatment. These HRQOL improvements were consistent with clinical efficacy results. The findings demonstrate that tolterodine IR patients experience overall improvement in their condition that resulted in important impacts on their HRQOL.

Health-Related Quality of Life Outcomes of Omeprazole versus Ranitidine in Poorly Responsive Symptomatic Gastroesophageal Reflux Disease

Objective: This study evaluated changes in health-related quality of life (HRQL) outcomes of once-daily omeprazole compared with ranitidine for the short-term treatment of patients with poorly responsive symptomatic gastroesophageal reflux disease (GERD). Methods: A double-blind, randomized clinical trial, compared omeprazole versus ranitidine for the treatment of poorly responsive GERD. Eligible patients had a history of predominant heartburn symptoms with symptomatic heartburn after 6 weeks of ranitidine treatment. Patients were randomized to omeprazole 20 mg once daily (n = 156) or ranitidine 150 mg twice daily (n = 161) and followed for 8 weeks. Assessments were completed at baseline and after 8 weeks with physician-rated symptoms: Gastrointestinal Symptom Rating Scale (GSRS); Psychological General Well-Being (PGWB) Index; Sleep Scale; Impact on Daily Activities Scale, and Overall Treatment Effect. Primary HRQL endpoints were the GSRS reflux scale and PGWB total score. Results: No differences between the 2 treatment groups were observed in baseline demographic, clinical or HRQL measures. After 8 weeks, omeprazole-treated patients had greater improvement in GSRS reflux scale scores (p<0.0001) and PGWB total scores (p = 0.019) compared with ranitidine-treated patients. Significant between group differences favoring omeprazole were also observed in GSRS total scores (p<0.0001), abdominal pain scale scores (p = 0.003), and indigestion scale scores (p = 0.003), Impact on Daily Activities (p = 0.001), PGWB positive well-being (p = 0.015), anxiety (p = 0.030), and general health scale scores (p = 0.010). Patient ratings of overall treatment effect demonstrated the significantly (p<0.0001) greater benefits of omeprazole (mean = 5.26) compared with ranitidine treatment (mean = 3.83). Conclusions: Omeprazole treatment significantly reduced persistent reflux-related symptoms and normalized psychological well-being compared with ranitidine in poorly responsive symptomatic patients with GERD.

Evaluating Health-related quality-of-life outcomes in patients with congestive heart failure. A review of recent randomised controlled trials.

Congestive heart failure (CHF) is a chronic disorder characterised by fatigue, shortness of breath and congestion. Treatment is designed to relieve symptoms, halt or delay progression of the disease, prolong life and, ultimately, improve quality of life. The purpose of this paper is to identify recent trends in the assessment of health-related quality-of-life (HR-QOL) outcomes in randomised, controlled trials evaluating treatment effectiveness in patients with CHF. 41 studies using HR-QOL as an explicit outcome and published in English between 1990 and September 1998 were reviewed. Trends in the measurement of HR-QOL and evidence of treatment effectiveness are presented followed by a discussion of the implications for future research. Results suggest that pharmacological and nonpharmacological treatment regimens can have a positive impact on HR-QOL. However, treatment-related improvement in exercise capacity in patients with CHF was not consistently associated with improvement in all domains of HR-QOL. The primary HR-QOL domain affected by treatment appears to be the performance of daily activities, which may or may not be accompanied by enhanced well-being. This suggests that functional status should be considered a primary HR-QOL end-point in clinical intervention trials. Preference-based or utility assessment, ethnic group differences in treatment effectiveness, caregiver burden and cost effectiveness are understudied outcomes in CHF research.