Assessing the clinical significance of health-related quality of life (HrQOL) improvements in anaemic cancer patients receiving epoetin alfa

doi:10.1016/S0959-8049(02)00628-7

European Journal of Cancer

Volume 39, Issue 3, February 2003, Pages 335-345

https://doi.org/10.1016/S0959-8049(02)00628-7 Get rights and content

Abstract

Health-related quality of life (HrQOL) assessments are gaining importance as outcome measures in cancer clinical trials. A recently published clinical trial reported statistically significant (P<0.001) increases in haemoglobin (Hb) levels and significantly (P<0.01) increased HrQOL scores following the administration of recombinant human erythropoietin (r-HuEPO, epoetin alfa) versus placebo to anaemic cancer patients who received non-platinum chemotherapy. This study employed five cancer-specific HrQOL instruments. Hb and HrQOL data from this trial were analysed to estimate the minimally important difference (MID) in HrQOL measures that could be interpreted as clinically meaningful, with Hb level selected as the best external standard. Patients were assigned to two groups: improved (Hb increases of ⩾1 g/dL) or stable (change in Hb of-1 g/dL to <1 g/dL). The MID was first determined as the difference between the mean changes in HrQOL in the improved group versus the stable group. By this analysis, the differences in HrQOL scores between the epoetin alfa group and the placebo group were clinically important for all Hb-sensitive, cancer-specific HrQOL evaluations. Linear regression analyses performed to provide estimates of the MID for specific values of Hb change confirmed that the differences in HrQOL scores between patient groups were clinically significant. These analyses were repeated using a data set from a separate clinical trial, which further supported the conclusion that observed HrQOL changes demonstrated in the multicentre, double-blind study were clinically important. These methods provide one means for interpreting the clinical relevance of changes in HrQOL evaluated in clinical trials.

Introduction

Health-related quality of life (HrQOL) assessments have become common as outcome measures in cancer clinical trials 1, 2, 3, and a number of previously validated instruments are available to assess HrQOL in cancer patients [4]. This trend signifies a widespread recognition that cancer patients face important changes in physical, psychological, and social functioning, overall well-being, and life satisfaction as a consequence of their disease and its treatments 2, 5. As a component of a clinical trial, the statistical significance of changes in HrQOL can be estimated using available analytical methods. There remains a need, however, to interpret the observed numerical differences from HrQOL instruments used in clinical trials in terms that have meaning to clinicians, administrators and patients. Better interpretation of HrQOL results from clinical trials would enable physicians to incorporate those results into their practices including standards of care [6]. More explicitly, there is a need to determine the minimally important difference (MID) in a HrQOL measure that will translate into a clinically meaningful outcome 1, 7, 8, 9, 10.

One factor known to contribute to diminished HrQOL in cancer patients is fatigue, which is often a symptom of anaemia 5, 11, 12, 13, 14. Fatigue and its sequelae, including loss of energy, restrictions in the ability to do daily activities, dizziness, and impaired cognitive function, are among the most frequently reported complaints of cancer patients arising from the disease, its treatment, or both 5, 11, 12, 13, 14, 15, 16. In a recent survey, the majority of cancer patients with a history of chemotherapy ranked fatigue as the side effect with the greatest impact on daily living [16]. The adverse effects of fatigue have been shown to involve many aspects of patients' quality of life, including relationships with friends and family and the employment status of both patients and caregivers 15, 16.

Hb levels, anaemia, and the symptomatic effects of anaemia correlate closely with HrQOL domains [10], and increases in Hb have been associated with increases in HrQOL in several trials 17, 18, 19, 20. Results from clinical studies have shown that recombinant human erythropoietin (r-HuEPO, epoetin alfa; epoetin alfa marketed as EPREX^®/ERYPO^®, Ortho Biotech, a division of Janssen-Cilag in Europe) can increase haemoglobin (Hb), reduce transfusion requirements, and improve HrQOL in patients, especially for cancer-specific domains such as fatigue, energy level and well-being 17, 18, 19, 20, 21, 22.

Full results from a recent multinational, double-blind, placebo-controlled, randomised trial that investigated the effects of epoetin alfa in anaemic cancer patients (N=375) who received non-platinum chemotherapy for non-myeloid malignancies have been previously published [19]. All patients gave written informed consent before study entry, and the study protocol and amendments were reviewed by an independent ethics committee. Mean Hb was significantly (P<0.001) increased in patients who received epoetin alfa (2.2 g/dL) compared with patients who received placebo (0.5 g/dL). Of interest to the current report are the observed effects of increased Hb on HrQOL. Changes in HrQOL for patients who received epoetin alfa or placebo were evaluated by the Functional Assessment of Cancer Therapy-General (FACT-G Total); fatigue subscale (FACT-An Fatigue subscale) of the FACT-Anemia scale (FACT-An); and Cancer Linear Analog Scale (CLAS, also known as the Linear Analog Scale Assessment, or LASA) for energy, ability to do daily activities, and overall QOL. The Medical Outcomes Study Short-Form 36 (SF-36) was also included as a generic HrQOL instrument and was scored into the Physical Component Summary (PCS) and Mental Component Summary (MCS). Statistically significant differences favouring epoetin alfa over placebo were seen for all primary cancer-specific HrQOL assessments by univariate analysis (range, P=0.0007 to P=0.0048, adjusted for multiple comparisons). For the two general scales (SF-36 PCS and MCS), differences in mean scores revealed trends favouring epoetin alfa and determined that no decrement in HrQOL was attributable to treatment [19].

Multiple linear regression analysis showed a significant (P<0.05) advantage for epoetin alfa over placebo for all five Hb-sensitive, cancer-specific scales adjusting for disease progression and other possible confounding variables, and confirmed the results of the univariate analysis [23]. Additionally, statistical significance (P<0.05) was shown for both cross-sectional correlation analysis between Hb and HrQOL for six of seven primary endpoints and for longitudinal analysis between Hb and all seven HrQOL scales (Table 1). The longitudinal correlation between Hb and HrQOL was assessed by deriving the Pearson correlation coefficient between the change in Hb and the change in HrQOL.

Additional analyses of these data were conducted to explore the clinical importance of the observed treatment effect of epoetin alfa on HrQOL. Results of these analyses are presented in this report.

Section snippets

Determining the minimally important difference

Because Hb is the biomarker most often employed to evaluate anaemia [24], it was selected as the external criterion most appropriate for interpretation of HrQOL changes associated with epoetin alfa. For this analysis, an Hb increase of 1 g/dL, which represents the clinical response that can be expected from transfusion of 1 unit of packed red blood cells, was considered to be the minimally important clinical change by which to evaluate HrQOL results 24, 25, 26.

Patients were pooled across

Results

Table 2 shows a comparison of (stable versus improved) MIDs and trial-reported differences in HrQOL change between treatment groups. For the FACT-G Total, the MID (i.e., the difference in HrQOL between patients with stable Hb (change of between −1.0 and 1 g/dL) and those with an Hb change ⩾1.0 g/dL) was 2.54. In the clinical trial, the difference in the FACT-G Total between the epoetin alfa-treated group and the placebo group was 6.06. Since the HrQOL difference seen in the trial was larger (in

Discussion

HrQOL instruments often produce results or scores that physicians are not able to evaluate concerning their clinical importance, such as they would with a clinical marker like a 10% increase in blood pressure [1]. Alternative means are therefore needed for interpreting these valuable gauges of patient well-being and functioning. Analysis of MID is a means of translating changes in an HrQOL instrument score into terms that are clinically meaningful [1]. The MID has been described as the

Conclusions

The MID for changes in HrQOL in anaemic cancer patients can be accurately assessed by relating changes to a 1 g/dL change in Hb level. Results from the analyses reported here have underscored the positive effect of epoetin alfa observed in the clinical trial, namely, that significantly increased Hb levels result in significantly increased HrQOL scores that are also clinically meaningful. Furthermore, the analyses of MID provide a valid method to give clinical relevance to changes in HrQOL as

Acknowledgements

We thank David Cella, Brenda Gillespie, and Diane Fairclough for their contribution to this analysis. This work was supported by a research grant from Johnson & Johnson Pharmaceutical Research and Development L.L.C., Raritan, NJ, USA and Ortho Biotech, a division of Janssen-Cilag, in Europe.

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Assessing the clinical significance of health-related quality of life (HrQOL) improvements in anaemic cancer patients receiving epoetin alfa

Abstract

Introduction

Section snippets

Determining the minimally important difference

Results

Discussion

Conclusions

Acknowledgements

Control Clin. Trials

J. Clin. Epidemiol.

J. Chronic Dis.

J. Clin. Epidemiol.

J. Clin. Epidemiol.

Eur. J. Cancer

J. Pain Symptom Manage.

J. Pain Symptom Manage.

J. Pain Symptom Manage.

Outcomes of cancer treatment for technology assessment and cancer treatment guidelines

J. Clin. Oncol.

Quality of life outcomesmeasurement and validation

Oncology

Factors influencing quality of life in cancer patientsanemia and fatigue

Semin. Oncol.

Interpreting the significance of changes in health-related quality of life scores

J. Clin. Oncol.

Assessing the responsiveness of a quality-of-life instrument and the measurement of symptom severity in essential hypertension

Pharmacoeconomics

Fatigue and the cancer experiencethe state of the knowledge

Oncol. Nurse Forum

Anemia in cancer patients

Semin. Oncol.