Andrew Bottomley

The Prognostic Significance of Patient-Reported Outcomes in Cancer Clinical Trials

PURPOSE Patient-reported outcomes (PROs), routinely collected as a part of cancer clinical trials, have been linked with survival in numerous clinical studies, but a comprehensive critical review has not been reported. This study systematically assessed the impact of PROs on patient survival after a cancer diagnosis within the context of clinical trials. DESIGN Cancer clinical trials that assessed baseline PROs and mortality were identified through MEDLINE (through December 2006) supplemented by the Cochrane database, American Society of Clinical Oncology/European Society for Medical Oncology abstracts and hand searches. Inclusion criteria were publication in English language and use of multivariate analyses of PROs that controlled for one or more clinical factors. Two raters reviewed each study, abstracted data, and assessed study quality; two additional raters verified abstractions. RESULTS In 36 of 39 studies (N = 13,874), at least one PRO was significantly associated with survival (P < .05) in multivariate analysis, with varying effect sizes. Studies of lung (n = 12) and breast cancer (n = 8) were most prevalent. The most commonly assessed PRO was quality of life, measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 in 56% of studies. Clinical variables adjusted for included performance status (PS), treatment arm, stage, weight loss, and serum markers. Results indicated that PROs provide distinct prognostic information beyond standard clinical measures in cancer clinical trials. CONCLUSION PROs might be considered for stratification purposes in future trials, as they were often better predictors of survival than PS. Studies are needed to determine whether interventions that improve PROs also increase survival and to identify explanatory mechanisms through which PROs relate to survival.

Quality of life research within the EORTC— the EORTC QLQ-C30

In forming its Quality of Life Group, the EORTC created one of the earliest and largest of such groups in Europe. The EORTC QLQ-C30 which this group developed has become the most widely used questionnaire in Europe for cancer patients, and is extensively used around the world. The Quality of Life Group continues to build upon this success, both by refining the QLQ-C30, whilst developing a range of additional modules, and by initiating research projects that explore aspects of quality of life assessment, evaluation and interpretation. We review the progress to date and indicate directions of further research and development.

Clinical and psychometric validation of an EORTC questionnaire module, the EORTC QLQ-OES18, to assess quality of life in patients with oesophageal cancer

Quality of life (QOL) assessment requires clinically relevant questionnaires that yield accurate data. This study defined measurement properties and the clinical validity of the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire module to assess QOL in oesophageal cancer. The oesophageal module the QLQ-OES24 and core questionnaire, the Quality of Life-Core 30 questionnaire (QLQ-C30) was administered patients undergoing treatment with curative (n=267) or palliative intent (n=224) and second assessments performed 3 months or 3 weeks later respectively. Psychometric tests examined scales and measurement properties of the module. Questionnaires were well accepted, compliance rates were high and less than 2% of items had missing data. Multi-trait scaling analyses and face validity refined the module to four scales and six single items (QLQ-OES18). Selective scales distinguished between clinically distinct groups of patients and demonstrated treatment-induced changes over time. The EORTC QLQ-OES18 demonstrates good psychometric and clinical validity. It is recommended for use with the core questionnaire, the QLQ-C30, to assess QOL in patients with oesophageal cancer.

Health-related quality of life in patients with glioblastoma: a randomised controlled trial

BACKGROUND A randomised controlled trial of radiotherapy alone versus radiotherapy with concomitant and adjuvant temozolomide for patients with glioblastoma showed that survival was higher for patients assigned combination treatment compared with those assigned standard radiotherapy alone. This paper reports the health-related quality of life (HRQOL) of the patients in this trial. METHODS 573 patients with newly diagnosed glioblastoma were randomly allocated either radiotherapy alone or radiotherapy and temozolomide. The primary endpoint was survival, and HRQOL was a secondary endpoint. We assessed HRQOL at baseline and at every 3 months during treatment until progression using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) and the EORTC brain cancer module (EORTC BN-20). We calculated changes from baseline score for seven predefined HRQOL measures (fatigue, overall health, social function, emotional function, future uncertainty, insomnia, and communication deficit) and differences between groups for these measures at every time point. The significance of, and proportions of patients with, improved HRQOL scores--defined as a change of 10 points or more--were recorded. This trial is registered on the US National Cancer Institute website http://www.cancer.gov/search/NewClinicalTrials, NCT00006353. FINDINGS Baseline questionnaires were available for 490 (86%) patients. Baseline HRQOL scores did not differ between groups. At first follow-up, groups differed only in social functioning, favouring the radiotherapy-only group (mean score 79.0 [SD 3.2] for patients assigned radiotherapy vs 67.4 [2.7] for those assigned radiotherapy and temozolomide; difference between groups 11.6 points [95% CI 3.5-19.7], p=0.0052). Over subsequent assessments, HRQOL was much the same between treatment groups. INTERPRETATION Addition of temozolomide during and after radiotherapy for patients with newly diagnosed glioblastoma significantly improved survival without a negative effect on HRQOL.

Beyond the Development of Health-Related Quality-of-Life (HRQOL) Measures: A Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials—Does HRQOL Evaluation in Prostate Cancer Research Inform Clinical Decision Making?

PURPOSE The aim of this study was to evaluate whether the inclusion of health-related quality of life (HRQOL), as a part of the trial design in a randomized controlled trial (RCT) setting, has supported clinical decision making for the planning of future medical treatments in prostate cancer. MATERIALS AND METHODS A minimum standard checklist for evaluating HRQOL outcomes in cancer clinical trials was devised to assess the quality of the HRQOL reporting and to classify the studies on the grounds of their robustness. It comprises 11 key HRQOL issues grouped into four broader sections: conceptual, measurement, methodology, and interpretation. Relevant studies were identified in a number of databases, including MEDLINE and the Cochrane Controlled Trials Register. Both their HRQOL and traditional clinical reported outcomes were systematically analyzed to evaluate their consistency and their relevance for supporting clinical decision making. RESULTS Although 54% of the identified studies did not show any differences in traditional clinical end points between treatment arms and 17% showed a difference in overall survival, 74% of the studies showed some difference in terms of HRQOL outcomes. One third of the RCTs provided a comprehensive picture of the whole treatment including HRQOL outcomes to support their conclusions. CONCLUSION A minimum set of criteria for assessing the reported outcomes in cancer clinical trials is necessary to make informed decisions in clinical practice. Using a checklist developed for this study, it was found that HRQOL is a valuable source of information in RCTs of treatment in metastatic prostate cancer.

An international field study of the EORTC QLQ-PR25: A questionnaire for assessing the health-related quality of life of patients with prostate cancer

AIM To evaluate the psychometrics of the EORTC QLQ-PR25, a questionnaire assessing the health-related quality of life of prostate cancer patients. METHODS The QLQ-PR25 and the QLQ-C30 were administered to 642 prostate cancer patients from 13 countries treated with curative or palliative intent. The QLQ-PR25 assesses urinary, bowel and sexual symptoms and functioning, and the side-effects of hormonal treatment. RESULTS Five hundred and nine patients were available for the final analysis. Multitrait scaling analyses confirmed the hypothesised scale structure of the QLQ-PR25. Internal consistency reliability was good (coefficient alpha=0.70-0.86) for the urinary symptoms and sexual function scales, but lower for the bowel function and side-effects of hormonal treatment scales (alpha<0.70). The module discriminated clearly between clinically distinct patient subgroups, and was responsive to changes in health status over time. CONCLUSION In general, the QLQ-PR25 demonstrates acceptable psychometric properties and clinical validity. Some caution should be used in interpreting the bowel function and side-effects of hormonal therapy scales; results can be reported at the individual item and scale level.

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

PURPOSE 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 AND METHODS 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. RESULTS 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). CONCLUSION 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.

An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients

AIMS The psychometric properties of the EORTC QLQ-BN20, a brain cancer-specific HRQOL questionnaire, have been previously determined in an English-speaking sample of patients. This study examined the validity and reliability of the questionnaire in a multi-national, multi-lingual study. METHODS QLQ-BN20 data were selected from two completed phase III EORTC/NCIC clinical trials in brain cancer (N=891), including 12 languages. Experimental treatments were surgery followed by radiotherapy (RT) and adjuvant PCV chemotherapy or surgery followed by concomitant RT plus temozolomide (TMZ) chemotherapy and adjuvant TMZ chemotherapy. Standard treatment consisted of surgery and postoperative RT alone. The psychometrics of the QLQ-BN20 were examined by means of multi-trait scaling analyses, reliability estimation, known groups validity testing, and responsiveness analysis. RESULTS All QLQ-BN20 items correlated more strongly with their own scale (r>0.70) than with other QLQ-BN20 scales. Internal consistency reliability coefficients were high (all alpha0.70). Known-groups comparisons yielded positive results, with the QLQ-BN20 distinguishing between patients with differing levels of performance status and mental functioning. Responsiveness of the questionnaire to changes over time was acceptable. CONCLUSION The QLQ-BN20 demonstrates adequate psychometric properties and can be recommended for use in conjunction with the QLQ-C30 in assessing the HRQOL of brain cancer patients in international studies.

Patient-reported outcomes: Assessment and current perspectives of the guidelines of the Food and Drug Administration and the reflection paper of the European Medicines Agency

AIMS Patient-reported outcomes (PROs) have recently gained greater credibility with regulatory bodies aiming to standardise their use and interpretation in RCTs, thereby supporting medicinal product submissions. For this reason, the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have released guidelines. This review paper provides an overview of the current perspectives and views on these guidelines. METHOD To evaluate the FDA and EMEA PRO guidelines, 47 expert responses to the FDA guidance were qualitatively reviewed. Two reviewers independently extracted data from these letters and checked these responses to warrant consistency and agreement in the evaluation process. A PubMed literature review was systematically examined to obtain supporting evidence or related articles for both the guidance documents. RESULTS Generally, there is agreement between regulatory authorities and the research community on the contents of the FDA and EMEA PRO draft guidance. However, disagreements exist on significant philosophical topics (e.g. the FDA focuses more on conceptual models and symptoms than the EMEA) and design topics (e.g. the FDA is more restrictive on issues of recall bias, blinding of oncology trials and degrees of psychometric validation than researchers and the EMEA). This could influence the approval of PRO claims. CONCLUSION PRO guidance from the EMEA and FDA has been valuable, and has raised the profile and active debate of PROs in oncology. However, our review of the current opinion shows that there are controversial aspects of the guidance. Consequently, greater latitude should be given to how the guidance is interpreted and applied.

An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-OV28) in assessing the quality of life of patients with ovarian cancer

This study defines the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire designed to measure the QOL of patients with ovarian cancer. The ovarian cancer module (EORTC QLQ-OV28) was developed to supplement the EORTC QLQ-C30. The core questionnaire and the QLQ-OV28 were prospectively administered to 368 ovarian cancer patients after they had been treated with radical or debulking surgery followed by chemotherapy. The QLQ-OV28 module assesses abdominal/gastrointestinal symptoms, peripheral neuropathy, other chemotherapy side-effects, hormonal/menopausal symptoms, body image, attitude to disease/treatment and sexual functioning. Questionnaires were well accepted by patients, baseline compliance rates were 86%, 72% provided a second assessment, less than 3% of the items had missing data. Multi-trait scaling analyses confirmed the hypothesised scales. All hypothesised scales exhibited good psychometric properties. These results support the clinical and psychometric validity of the EORTC QLQ-OV28 module as a supplement to the EORTC QLQ-C30.