Minimally important differences for interpreting the EORTC QLQ-C30 in patients with advanced colorectal cancer treated with chemotherapy.

AIM: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) assesses the health-related quality of life of patients in cancer trials. There are currently no minimally important difference (MID) guidelines for the EORTC QLQ-C30 for colorectal cancer (CRC). This study aims to estimate MIDs for the EORTC QLQ-C30 scales in patients with advanced CRC treated with chemotherapy and enrolled in clinical trials. METHOD: The data were obtained from three published EORTC trials that treated CRC patients using chemotherapy. Potential anchors were selected from clinical variables based on their correlation with EORTC QLQ-C30 scales. Anchor-based MIDs for within-group change and between-group change were estimated via the mean change method and linear regression, respectively, and summarized using weighted correlation. Distribution-based MIDs were also examined. RESULTS: Anchor-based MIDs were determined for deterioration in 8 of the 14 EORTC QLQ-C30 scales and in 9 scales for improvement, and varied by scale, direction of change and anchor. MIDs for improvement (deterioration) ranged from 6 to 18 (-11 to -5) points for within-group change and 5 to 15 (-10 to -4) for between-group change. Summarized MIDs (in absolute values) per scale mostly ranged from 5 to 10 points. CONCLUSIONS: These findings have clinical relevance for the interpretation of treatment efficacy and the design of clinical trials by informing sample size requirements.

Does change in health-related quality of life score predict survival? Analysis of EORTC 08975 lung cancer trial.

BACKGROUND: Little is known about whether changes in health-related quality of life (HRQoL) scores from baseline during treatment also predict survival, which we aim to investigate in this study. METHODS: We analysed data from 391 advanced non-small-cell lung cancer (NSCLC) patients enrolled in the EORTC 08975 study, which compared palliative chemotherapy regimens. HRQoL was assessed at baseline and after each chemotherapy cycle using the EORTC QLQ-C30 and QLQ-LC13. The prognostic significance of HRQoL scores at baseline and their changes over time was assessed with Cox regression, after adjusting for clinical and socio-demographic variables. RESULTS: After controlling for covariates, every 10-point increase in baseline pain and dysphagia was associated with 11% and 12% increased risk of death with hazard ratios (HRs) of 1.11 and 1.12, respectively. Every 10-point improvement of physical function at baseline (HR=0.93) was associated with 7% lower risk of death. Every 10-point increase in pain (HR=1.08) was associated with 8% increased risk of death at cycle 1. Every 10-point increase in social function (HR=0.91) at cycle 2 was associated with 9% lower risk of death. CONCLUSIONS: Our findings suggest that changes in HRQoL scores from baseline during treatment, as measured on subscales of the EORTC QLQ-C30 and QLQ-LC13, are significant prognostic factors for survival.

Sexual quality of life in Hodgkin Lymphoma: a longitudinal analysis by the German Hodgkin Study Group.

BACKGROUND: Health-related quality of life (HRQoL) comprises different domains of physical, mental, and social well-being. In this analysis, we focus on sexual quality of life in Hodgkin Lymphoma (HL) patients. METHODS: Four-thousand one-hundred and sixty patients enroled in the HD10-HD12 trials underwent HRQoL assessment. Instruments included the Quality of Life Questionnaire for survivors (QLQ-S), combining the European Organisation for Research and Treatment of Cancer QLQ-C30, Multidimensional fatigue (FA) inventory (MFI-20) and an additional sexual functioning (SX) scale. We describe SX up to 27 months after therapy and analyse relationship to stage, age, gender, FA, social functioning, and therapy. Statistical methods range from descriptive statistics to a classification of SX courses, and a longitudinal structural equations model with full information maximum likelihood estimation of missing data. In the analysis, a score below 50 was used to describe severe sexual dysfunction. RESULTS: Three-thousand two-hundred and eight patients provided data on SX. Patients in advanced stages reported lower SX than patients in early stages both, before and after the treatment. During follow-up, an improvement of SX compared with baseline was detected, except for those ≥50 years. Patients in early stages reached normal SX, whereas advanced-stage patients remained below the reference value for healthy controls. Sexual functioning during follow-up was significantly and strongly related to previous SX, other HRQoL measures, age, and stage, and to lesser degree with gender and chemotherapy. CONCLUSION: Overall, HL patients have a decreased sexual quality of life at baseline, which improves after therapy and normalises in early-stage patients. Importantly, long-term SX is more closely related to patient characteristics and SX at baseline than to the intensity of treatment.

Effect of completion-time windows in the analysis of health-related quality of life outcomes in cancer patients.

BACKGROUND: We examined if cancer patients' health-related quality of life (HRQoL) scores on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 are affected by the specific time point, before or during treatment, at which the questionnaire is completed, and whether this could bias the overall treatment comparison analyses. PATIENTS AND METHODS: A 'completion-time window' variable was created on three closed EORTC randomised control trials in lung (non-small cell lung cancer, NSCLC) and colorectal cancer (CRC) to indicate when the QLQ-30 was completed relative to chemotherapy cycle dates, defined as 'before', 'on' and 'after'. HRQoL mean scores were calculated using a linear mixed model. RESULTS: Statistically significant differences (P<0.05) were observed on 6 and 5 scales for 'on' and 'after' comparisons in the NSCLC and two-group CRC trial, respectively. As for the three-group CRC trial, several statistical differences were observed in the 'before' to 'on' and the 'on' to 'after' comparisons. For all three trials, including the 'completion-time window' variable in the model resulted in a better fit, but no substantial changes in the treatment effects were noted. CONCLUSIONS: We showed that considering the exact timing of completion within specified windows resulted in statistical and potentially clinically significant differences, but it did not alter the conclusions of treatment comparison in these studies.

Minimal clinically meaningful differences for the EORTC QLQ-C30 and EORTC QLQ-BN20 scales in brain cancer patients.

BACKGROUND: We aimed to determine the smallest changes in health-related quality of life (HRQoL) scores in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 and the Brain Cancer Module (QLQ-BN20), which could be considered as clinically meaningful in brain cancer patients. MATERIALS AND METHODS: World Health Organisation performance status (PS) and mini-mental state examination (MMSE) were used as clinical anchors appropriate to related subscales to determine the minimal clinically important differences (MCIDs) in HRQoL change scores (range 0-100) in the QLQ-C30 and QLQ-BN20. A threshold of 0.2 standard deviation (SD) (small effect) was used to exclude anchor-based MCID estimates considered too small to inform interpretation. RESULTS: Based on PS, our findings support the following integer estimates of the MCID for improvement and deterioration, respectively: physical (6, 9), role (14, 12), and cognitive functioning (8, 8); global health status (7, 4*), fatigue (12, 9), and motor dysfunction (4*, 5). Anchoring with MMSE, cognitive functioning MCID estimates for improvement and deterioration were (11, 2*) and for communication deficit were (9, 7). Estimates with asterisks were <0.2 SD and were excluded from our MCID range of 5-14. CONCLUSION: These estimates can help clinicians evaluate changes in HRQoL over time, assess the value of a health care intervention and can be useful in determining sample sizes in designing future clinical trials.

[Assessing psychopathic personality disorders for legal procedures for using a version for adolescents of Hare's revised checklist]. / Erfassung von Persönlichkeitsdimensionen der Psychopathy nach Hare bei der strafrechtlichen Begutachtung von Jugendlichen. Eine retrospektive Untersuchung zur Anwendbarkeit der Psychopathy-Checkliste als Version für Jugendliche.

In accordance with Robert Hare's concept, the term psychopathy was operationalized in 1985 when the revised form of the psychopathy checklist (PCL-R) was published. Since then, the PCL-R has been used internationally. For several years in North America and now even in England and the Netherlands, personality traits of psychopathy have also been studied in children and juveniles. Based on the PCL-R, a checklist for adolescents (PCL-YV) was developed that takes the special conditions of adolescents into account. The goal of this paper was to test the applicability of the PCL-YV retrospectively in a sample of forensic psychiatric evaluations of delinquent juveniles that were assigned to the Clinic for Child and Adolescent Psychiatry at the University of Cologne, Germany. Based on results collected with the PCL-YV, data on groups of low- and medium-scoring juveniles were classified which partially differed significantly in relation to sociodemographic and anamnestic data. Furthermore, factor analyses showed a three-factor model solution. Associations with legal issues such as the question of criminal responsibility could not be found. In summary, the results indicate the applicability of the PCL-YV for adolescents but show the difficulties of retrospective design without conducting PCL interviews.

Health related quality of life outcomes in cancer clinical trials.

Over the last decade, health related quality of life (HRQOL) investigations have become an increasingly important part of many cancer clinical trial research programs. This paper presents a review of all HRQOL studies published by the European Organisation for Research and Treatment of Cancer (EORTC), one of the largest clinical trials organisations in Europe. The findings highlight 24 clinical trials that have been published to date, enrolling over 9000 patients. HRQOL is fully integrated into EORTC phase III trials. In many trials, HRQOL provides a valuable source of additional information useful to both clinician and patient when making treatment decisions. Furthermore, several trials have found that the combined use of clinical information along with HRQOL data has led to the development of new standards of care in several different cancer sites. With more than 40 ongoing HRQOL studies in the EORTC, we expect HRQOL to play an even greater role over the coming decade in helping establish the optimal treatment and care approach for cancer patients.

Fatigue in long-term survivors of Hodgkin's lymphoma; a report from the German Hodgkin Lymphoma Study Group (GHSG).

Although treatment regimens for Hodgkin's lymphoma have become more sophisticated, little is known about the prevalence of fatigue in long-term survivors. Therefore, we investigated the fatigue status of long-term survivors of Hodgkin's lymphoma and a control group using a pre-validated questionnaire. In 1995/1996, we contacted 1981 patients, who were enrolled in the German Hodgkin Studies HD 1-6. All patients were treated according to the treatment protocols HD1-3 (1981-1988) and HD 4-6 (1988-1993). The patients with a current status of complete remission were asked to complete a quality-of-life (QoL) questionnaire (European Organisation for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ C-30)) and a fatigue questionnaire (Multidimensional Fatigue Inventory (MFI)). The results were compared with the data from 935 controls, matched for age, gender and living area. Eight-hundred and eighteen questionnaires from the patients were available for analysis. The median time between the end of treatment and completing the questionnaire is 5.2 years. Fatigue levels of patients with Hodgkin's lymphoma are high, even years after treatment. Fatigue dimensions are significantly influenced by several clinical and non-clinical factors. Fatigue levels of Hodgkin's lymphoma patients are significantly higher than those of the control group. Further investigations are warranted to explore the effectiveness of treatment strategies for fatigue.

Recombinant human erythropoietin, epoetin beta, in patients with relapsed lymphoma treated with aggressive sequential salvage chemotherapy--results of a randomized trial.

The aim of the study was to investigate the effects of erythropoietin (epoetin beta) on red blood cell (RBC) transfusions, hemoglobin (Hb) levels, and quality of life (QOL) in patients with relapsed lymphoma treated with an aggressive sequential salvage chemotherapy (SSCT) regimen. Sixty patients with early or late relapsed Hodgkin's disease ( n=39) or first relapse of aggressive non-Hodgkin's lymphoma ( n=21) were randomized to receive epoetin beta 10,000 IE subcutaneously three times a week or no epoetin during salvage chemotherapy. Patients in both study arms received two cycles of DHAP (dexamethasone, high-dose cytarabine, cisplatin); patients in partial remission (PR) or complete remission (CR) then received cyclophosphamide, followed by peripheral blood stem cell (PBSC) harvest, methotrexate plus vincristine, and etoposide. The final myeloablative course was BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by autologous stem cell support. The primary endpoint of the study was the number of RBC units needed during SSCT. In addition, Hb levels and QOL were measured. The mean number of RBC units given in the epoetin beta arm was 4.5 compared to 8.3 in the control arm ( P=0.0134). The mean Hb levels during therapy were 10.4 g/dl in the epoetin beta arm and 9.7 g/dl in the control ( P=0.018). From baseline until BEAM therapy QOL (EORTC QLQ C30) and fatigue (MFI) assessment showed little QOL worsening or stable levels in both arms with a steeper increase of fatigue levels in the control group. Patients with relapsed lymphoma undergoing aggressive chemotherapy and stem cell support benefited from epoetin beta therapy, with a decrease of RBC transfusion requirements and lower rise of fatigue levels.

[Cancer fatigue syndrome]. / Das Krebs-Fatigue-Syndrom.

Tumour-related fatigue, which occurs in almost all tumour patients under therapy--very often even years after a successful therapy--has a considerable impact not only on the quality of life, but apparently also on the course and outcome of treatment. There is little known about where cancer fatigue syndrome comes from. Medical research is required particularly for the continuous states of tiredness persisting for years. The questionnaires currently in use permit an accurate evaluation of the existence and the course of tumour-related fatigue. The treatment of the cancer fatigue syndrome includes the correction of underlying metabolic disorders as well as--even more importantly--physical training and psycho-oncological measures in order to better cope with the disease. Many questions, however, are left open, for instance the impact of cancer fatigue syndrome on disability pensions of tumour patients. The German Fatigue Society (DfaG) was therefore founded in March 2002 in order to find out the correlations between these questions and the cancer fatigue syndrome.

Model-based methodology for analyzing incomplete quality-of-life data and integrating them into the Q-TWiST framework.

BACKGROUND: The standard Q-TWiST approach defines a series of health states and weights each state's duration according to its quality of life (QOL) to calculate quality-adjusted lifetimes. However, a fixed weight may not adequately reflect time variations in QOL. METHODS: To account for measurements derived from irregular visits and informative missing data, the authors estimated the mean QOL profile using a mixed-effect growth curve model for the response, combined with a logistic regression model for the drop-out process. RESULTS: Using data from a clinical study of lymphoma patients, the authors demonstrated better readaptation to normal life for patients younger than 30. Sensitivity analyses and computer simulations demonstrated that modeling the drop-out probability as a function of the QOL measurements is necessary if conditioning by health state is not possible. CONCLUSION: Our model-based approach is useful to analyze studies with incomplete QOL data, especially when approximate QOL assessment by health state is not possible.

The challenges and achievements involved in implementing Quality of Life research in cancer clinical trials.

Over the last decade, Quality of Life (QOL) research has become an important aspect of cancer clinical trials. A dramatically increasing number of published studies, both randomised and non-randomised, report QOL outcomes. There is increasing evidence that QOL results impact on both future research and treatment decisions for clinicians. The rising number of studies with QOL components is mirrored within the European Organization for Research and Treatment of Cancer (EORTC), one of the largest cancer clinical trial organisations in Europe. Clinical trial groups have frequently reported on the difficulties and challenges of implementing QOL research. In the following paper, we therefore examine past experience in EORTC QOL studies, with a focus on the challenges presented and the improved approaches that are being implemented to obtain more meaningful outcomes.

Quality of life in children with traumatic brain injury--basic issues, assessment, and recommendations.

An international Task Force was convened under the guidance of BMBF Conference so as to review the "State of the art" for measuring quality of life (QoL) in children who have suffered traumatic brain injury (TBI). After expert review of instruments and evaluation of two independent literature reviews this work group established "inclusion criteria" for the review of current tools that could contribute to the measurement of QoL in children with TBI. Six instruments were determined to meet all or most of the criteria required to be used in current clinical practice and research for children with TBI.

The development and utilisation of the European Organisation for research and treatment of cancer quality of life group item bank.

One of the problems in assessing patients' quality of life (QL) is the availability of good robust measures that have demonstrated validity, reliability and sensitivity for changes over time, but also have been validated across a large group of culturally diverse nations. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group (QLG) has recognised this and has established a substantial research programme with the aim of developing such tools, with particular relevance to cancer clinical trials. However, the management of a large set of items in multiple languages is difficult and very labour-intensive. Thus, to support the EORTC QLG research agenda, a computerised web-based database of all EORTC QLG measures and individual questionnaire items was developed. This database allows access to a pool of over 500 validated items in some 6000 translated versions. The database speeds up module development, ensures that questionnaires items have similar wording and provides rapid access to multiple translations.

Hodgkin's disease in the elderly: current status and future directions.

In general, it was agreed that high rates of toxicities during treatment occur in the elderly and that there is a frequent occurrence of early relapse. It is clear that different combinations of effective therapies with lower toxicity are required. It was felt, however, that certainly in the 60-70 year age group, approaches should be vigorous to and the same diagnostic and staging procedures as in younger individuals, but with much closer monitoring of toxicity and response to treatment. It was felt that as part of the approach, liberal support with haemopoeitic growth factors (G-CSF) was necessary to reduce prolonged neutropenia. It is important to understand that age in general is not a contrary indication for aggressive treatment and that biologically younger patients under the age of 65 years, in good physical and mental condition, often should be given with stage-adapted treatment, analogous to conventional treatment protocols for the <60 years age group. It was also considered that, in patients who clearly could not accept conventional treatment, study groups could begin to define the best palliative care for patients with pre-existing organ impairment, and that in all situations of assessment, whether in trial or not, there should be a detailed prospective assessment of quality of life parameters.

[Quality of life in oncological studies]. / Lebensqualität in onkologischen Studien.

During the past 20 years many efforts were made in oncology to establish quality-of-life research within clinical trials. The first step was to introduce research questions regarding the quality of life (QoL) of patients into the clinical oncological study context. Particularly after publication of the QLQ C 30 questionnaire by the EORTC Quality of Life Study Group a valid and reliable standard instrument for QoL evaluation was available, and many study groups started to include research questions on QoL in their trial protocols. However, it became obvious during the last years that the necessary integration of these methods into the treatment-oriented study protocols was only in part successful. Although QoL is mentioned more and more as a primary or secondary endpoint, the number of investigations that actually employ QoL for answering clinically relevant questions is still very limited. Moreover, under the growing economic pressure in health care during the last years, a shift occurred towards the development of 'general health measures' and towards the economic evaluation of treatment outcome. These developments are very closely linked to quality control and quality assurance issues in regard to the structures of medical decision making. The implications of these developments for QoL research in oncology are addressed.

Quality of life evaluation in oncological clinical trials - the EORTC model. The EORTC Quality of Life Study Group.

The European Organization for Research and Treatment of Cancer (EORTC) has taken a leading role in the development of the methodology of quality of life (QL) measurement. In the EORTC Quality of Life Study Group (QLSG) valid instruments to assess QL in a general manner and disease-specific modules have been developed to be used in oncological clinical trials. Statistical and methodological aspects of QL research are discussed. The application of QL assessments in clinical trials represents a subsequent challenge. To improve the practice of QL assessment in clinical trials an 'EORTC model' has been developed. This model requires the collaboration of liaison persons, the EORTC Cooperative Tumour Groups and the EORTC Data Centre Quality of Life Unit (QL Unit). Cooperation between these parties, protocol development and advantages and concerns of the model are mentioned in this paper. Finally, suggestions for improvement are proposed.

RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell tumors? Results of a prospective multicenter trial including quality of life assessment.

BACKGROUND: In order to reduce therapy-related morbidity in patients with nonseminomatous testicular germ cell tumors in clinical stage IIA/B, we performed a prospective multicenter trial comparing the standard retroperitoneal lymph node dissection (RPLND) +2 cycles of chemotherapy (arm A) with 3-4 cycles of primary chemotherapy (arm B). METHODS: From February 1991 to July 1995, 57 participating centers from Germany and Austria recruited 187 evaluable patients. 109 received primary RPLND and 78 primary chemotherapy. Two different chemotherapies were applied (PEB and CEB as adjuvant or inductive treatment). The quality of life (QoL), therapy-related morbidity, suspected predictive factors (histology and size of metastases), and outcome were assessed. RESULTS: In arm A, 12% had pathological stage (PS) I, 70% PS II A/B, and 18% PS II C/III. In arm B, 67% achieved complete remission with chemotherapy alone, 33% required a secondary RPLND. After a median follow-up of 36 months, 7% of the patients in arm A and 11% in arm B had relapsed. Two patients died due to complications of chemotherapy. Surgical complications amounted to 12% in arm A and 27% of 26 postchemotherapy RPLNDs (9% in arm B). Loss of ejaculation occurred in 32% in arm A, and 16% in arm B. Acute toxicity of chemotherapy was higher in the group receiving primary chemotherapy. CONCLUSION: We recommend primary RPLND because adjuvant chemotherapy can be spared in PS I, two cycles of chemotherapy are less toxic than 3 or 4 cycles, the primary operation is associated with less complications than that following chemotherapy and, with modern surgical procedures, ejaculation can be preserved in most of the patients, provided that the operation is carried out by an experienced surgeon. No statistically significant differences in the QoL outcome occurred between the treatment groups, suggesting that chemotherapy alone is not superior to primary or secondary RPLND in this respect.

Quality of life assessment in Hodgkin's disease: a new comprehensive approach. First experiences from the EORTC/GELA and GHSG trials. EORTC Lymphoma Cooperative Group. Groupe D'Etude des Lymphomes de L'Adulte and German Hodgkin Study Group.

Previous reports from available trials have dealt with negative long-term sequelae in Hodgkin's disease (HD) survivors. There is, however, a lack of longitudinal data showing the correlation between outcome and various treatment-related variables and the process of re-adaptation into normal life after the end of treatment. In order to investigate the quality of life (QoL) of patients with HD in different dimensions during active treatment and follow-up and to identify longitudinal patterns of QoL dimensions during re-adaptation to normal life within the EORTC Lymphoma Cooperative Group and Groupe D'Etude des Lymphomes de L'Adulte (EORTC/GELA) and the German Hodgkin Study Group (GHSG), QoL assessment strategies were put into use over the last three to five years. Furthermore, the efforts aimed at obtaining cross-cultural comparisons between the participating countries and study groups (EORTC/GELA and GHSG). Within the randomised EORTC/GELA Trial 'H8' for clinical stage I-II HD which started in September 1993, patients receive a QoL questionnaire for completion at each follow-up visit during the first 10 years after the end of active therapy. The corresponding 'HD8' study of the GHSG employs the assessment of QoL during and after active treatment periods. Within both studies, the EORTC QLQ C30 is used for QoL assessment incorporated in the QLQ-S (quality of life questionnaire for survivors), which additionally addresses the aspects of fatigue/malaise, sexuality, specific side effects, and retrospective evaluation of treatment. In total the QLQ-S includes 45 questions on 14 functional, symptom, and fatigue scales, 15 additional single items, and 3 open questions. In addition to the longitudinal QoL assessment, the GHSG carried out cross-sectional QoL trials with all cured surviving patients from the past HD1-6 studies and a matched normal control sample employing the QLQ-S and the life situation questionnaire (LSQ), an instrument covering objective data from 45 domains of life. To date, within the trials H8 and HD8 over 3000 QoL questionnaires from more than 800 patients from ten countries are available for analysis. Replication of the psychometric properties of the scales revealed satisfactory results using factor analyses and reliability testing across languages for the QLQ-S. A feasibility analysis showed generally a good acceptance of the questionnaire by the patients and physicians. QoL assessment within international multicentre trials in HD proved feasible within the two differently organised study groups of EORTC/GELA and GHSG. The use of subjective QoL data (QLQ-S) together with objective data (LSQ) in a combined cross-sectional and longitudinal trial system will give the most comprehensive insight into the problems of the re-integration process into normal life after cure. This information will provide the basis for the development of remedies/help measures and possible modifications of treatment strategies. The current approach will be further developed in close collaboration between both trial groups, and next steps will include translation of the LSQ into other languages and adaptation to various cultural circumstances.