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Journal of Clinical Oncology, Vol 22, No 13 (July 1), 2004: pp. 2576-2586 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.02.037 Randomized, Controlled Trial Investigating Short-Term Health-Related Quality of Life With Doxorubicin and Paclitaxel Versus Doxorubicin and Cyclophosphamide As First-Line Chemotherapy in Patients With Metastatic Breast Cancer: European Organization for Research and Treatment of Cancer Breast Cancer Group, Investigational Drug Branch for Breast Cancer and the New Drug Development Group StudyFrom the Quality of Life Unit, European Organization for Research and Treatment of Cancer Data Center, Insitut Jules Bordet, Brussels, Belgium; Institute of Oncology, Ljubljana, Slovenian; Weston Park Hospital, Sheffield; Newcastle General Hospital, Newcastle-upon-Tyne; and Cancer Research United Kingdom Department of Medical Oncology, Glasgow, United Kingdom; Instituto Regina Elena, Roma, Italy; and Centre Georges Francois Leclerc, Dijon Cedex, France Address reprint requests to Andrew Bottomley, European Organization for Research and Treatment of Cancer Data Center, Quality of Life Unit, Ave Mounier, 83 Bte11, 1200 Brussels, Belgium; e-mail: abo{at}eortc.be
PURPOSE: To compare health-related quality of life (HRQOL) in patients with metastatic breast cancer receiving the combination of doxorubicin and paclitaxel (AT) or doxorubicin and cyclophosphamide (AC) as first-line chemotherapy treatment. PATIENTS AND METHODS: Eligible patients (n = 275) with anthracycline-naive measurable metastatic breast cancer were randomly assigned to AT (doxorubicin 60 mg/m2 as an intravenous bolus plus paclitaxel 175 mg/m2 as a 3-hour infusion) or AC (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2) every 3 weeks for a maximum of six cycles. Dose escalation of paclitaxel (200 mg/m2) and cyclophosphamide (750 mg/m2) was planned at cycle 2 to reach equivalent myelosuppression in the two groups. HRQOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and the EORTC Breast Module at baseline and the start of cycles 2, 4, and 6, and 3 months after the last cycle. RESULTS: Seventy-nine percent of the patients (n = 219) completed a baseline measure. However, there were no statistically significant differences in HRQOL between the two treatment groups. In both groups, selected aspects of HRQOL were impaired over time, with increased fatigue, although some clinically significant improvements in emotional functioning were seen, as well as a reduction in pain over time. Overall, global quality of life was maintained in both treatment groups. CONCLUSION: This information is important when advising women patients of the expected HRQOL consequences of treatment regimens and should help clinicians and their patients make informed treatment decisions.
Metastatic breast cancer is one of the most common cancers in women. Worldwide, more than 570,000 new cases occur annually.1 Although new treatments may improve survival, one of the key issues is ensuring that patients have a worthwhile health-related quality of life (HRQOL).2 Nevertheless, many clinical trials in metastatic breast cancer have been published without HRQOL data.3 Unfortunately, such studies do not weigh the benefits of treatment and may have prolonged survival against the negative effects on HRQOL, which can impair clinical decision making.4 In addition, recent intriguing evidence suggests HRQOL itself may be a useful prognostic factor predicting survival in patients with metastatic breast cancer.5 There are many reasons why HRQOL is often not integrated into metastatic breast cancer studies.6,7 At the simplest level, there are significant barriers and confusion regarding the concept of HRQOL, which may have hindered its acceptance.8 However, now it is often regarded as a multidimensional construct, encompassing subjective clinical perceptions of positive and negative aspects of patient domains, including physical, emotional, social, and cognitive functions, and more importantly, disease symptoms and therapy.6 Other reasons for the failure to incorporate HRQOL include lack of resources, lack of investigator motivation, and poor knowledge of HRQOL issues. The present study examines the short-term HRQOL of patients with metastatic breast cancer receiving first-line chemotherapy for metastatic disease. They were treated with either a standard chemotherapy regimen of doxorubicin and cyclophosphamide (AC) or the newer combination of doxorubicin and paclitaxel (AT), with an incorporated planned escalation of the paclitaxel and cyclophosphamide. With AC, patients have a median time to progression of 6 to 9 months9,10 and can experience significant treatment-related side effects, including myelotoxicity, nausea/vomiting, and mucositis.11 The present study began in 1996 when clinicians believed that AT might improve clinical outcomes, such as disease-free status or improved survival. However, it was recognized that this new combination might induce additional treatment-related problems, with a negative influence on HRQOL.12,13 The hypothesis was therefore to explore the consequences of treatment and disease over time within both groups. In addition, this was accompanied by an exploratory prognostic factor survival analysis on four of the prespecified key HRQOL domains.
Treatment For this international, multicenter study (European Organization for Research and Treatment of Cancer [EORTC] trial 10961), patients were randomly assigned at the EORTC Data Center, Brussels, Belgium. After stratification for center, prior chemotherapy (none or adjuvant), performance status (Eastern Cooperative Oncology group 0 or 1 to 2), and presence of bone metastases (yes or no), patients were randomly assigned to receive either AT (doxorubicin 60 mg/m2 as an intravenous bolus plus paclitaxel 175 mg/m2 given as a 3-hour infusion starting 30 minutes after the end of doxorubicin) or AC (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2). Patients assigned to AT received premedication with dexamethasone 20 mg, administered orally 12 and 6 hours before therapy, diphenhydramine 50 mg, and cimetidine 300 mg or ranitidine 50 mg administered intravenously 30 minutes before paclitaxel. Treatment was scheduled for every 3 weeks. Full details were reported by Biganzoli et al.14 The trial, approved by the EORTC protocol review committee and the ethics committee of each participating center, was conducted in compliance with the Helsinki declaration. All patients provided written informed consent.
HRQOL Evaluations The EORTC QLQ-C30 measure (version 2) comprises five functioning scales (physical, role, emotional, cognitive, and social), three symptom scales (fatigue, nausea/vomiting, and pain), six single-item scales (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and the global quality-of-life (QOL) scale. The EORTC Breast Cancer Module (QLQ-BR23) is designed for use with patients with different stages of disease and treatment modality (surgery, chemotherapy, radiotherapy, and hormonal treatment).16 The module incorporates 23 questions grouped into five multi-item scales to assess systemic therapy side effects, arm symptoms, breast symptoms, body image, and sexual functioning. Sexual enjoyment, upset by hair loss, and future perspectives are assessed as single items. The items on both measures were scaled and scored using the recommended EORTC procedures.23 Raw scores were transformed to a linear scale ranging from 0 to 100, with a higher score representing a higher level of functioning or higher level of symptoms. Provided at least half of the items in the scale were completed, the scale score was calculated using only those items for which values existed. Because it is difficult to accurately assess financial costs in an international trial, and the fact that this was not a concern in our analysis, the financial impact of treatment was not included in the analysis. Given that there may be negative short-term treatment-related influence, and in order to reduce multiple testing, we selected five scales for the primary analysis: global QOL, fatigue, nausea and vomiting, upset by hair loss, and systemic therapy side effects. Other HRQOL variables were then examined on an exploratory basis. The results of this study are presented in accordance with recent guidelines for reporting HRQOL.24
On the basis of the work by Osoba et al,25 differences of at least 10 points (on a 0 to 100 scale) were classified as the minimum clinically meaningful change in a HRQOL parameter. For example, an increase by The group of patients having baseline and follow-up HRQOL data provided 93.7% power to detect a 10-point shift on the overall HRQOL scale using a two-sided test at the 5% significance level. This posthoc estimation of the power is based on the average observed value and its SE (mean, 57; SE = 2.4). Assessments were performed at baseline, in other words, at most 2 weeks before the randomization and before treatment, at cycles 2, 4, and 6, with time windows of ± 1 week. A final assessment was undertaken 3 months after the last cycle, with a time window of 10 weeks (± 5 weeks).
Procedure for Collecting HRQOL Data
Statistical Analysis In addition, an exploratory prognostic factor analysis was conducted on four of the key five preselected HRQOL scales; global QOL, fatigue, nausea and vomiting, upset by hair loss, and systemic effects. We excluded the item "upset by hair loss," as this was unlikely to be of any prognostic value. The Cox proportional hazards regression model, with stratification for treatment arm and important clinical prognostic factors (bone metastases, performance status, and prior chemotherapy), was used for both univariate and multivariate analysis of survival, with significance levels set at P = .05.
Between November 1996 and February 1999, 275 patients from 24 institutions were randomly assigned to receive AT (138 patients) or AC (137 patients). Of these patients, 114 (AT) and 105 (AC) had baseline HRQOL measures completed and were included in the analysis. The compliance for both measures was nearly identical. The characteristics of those in each treatment group with HRQOL assessments are presented in Table 1. There were no significant differences in the characteristics of the patients in each treatment group.
Clinical Results The clinical results have recently been reported elsewhere.14 Briefly, a median number of six cycles were delivered in both treatment arms. The relative dose-intensity and delivered cumulative dose of doxorubicin were lower in the AT arm.14 Median progression-free survival was 6 months in both treatment arms (P = .65). The response rates were 58% and 54% (P = .51), with median overall survival of 20.6 and 20.5 months for the AT and AC arms, respectively (P = .49). The AT regimen was characterized by a higher incidence of febrile neutropenia (32% v 9%) and decrease in left ventricular ejection fraction (27% v 14%). No differences in the efficacy study end points were observed. Treatment-related toxicity compromised doxorubicin-delivered dose-intensity in the paclitaxel-based regimen.
Compliance With HRQOL Measures
Of the 922 HRQOL forms received, 254 (from 125 patients) fell outside of the time assessment windows. Of these, 68 were from the last assessment point (ie, 3 months plus 5 weeks). For five patients, none of their HRQOL forms fell inside the designated time windows. Completed forms falling outside of the time assessment windows were excluded.
HRQOL Scale Results
On the five scales selected a priori, no significant differences between the two groups were seen (Fig 3). However, over the course of treatment, there appeared a significant time effect in both groups for these scales (P < .0001), except for "upset by hair loss" (P = .0475) and global QOL (P = .3816). "Upset by hair loss" was problematic, as only 28 patients initially completed this at baseline, thus making this of limited value. Using our criteria for clinically significant results of changes of more than 10 mean points, fatigue increased in both arms by the second assessment, decreased in the AC arm to levels comparable with baseline, but remained moderately clinically meaningful in the AT arm. In both groups, scores for nausea and vomiting increased at cycle 2 to clinically worse levels, but returned to levels comparable with baseline at the next assessment (cycles 4, 6). Also, in both groups, moderate clinically significant increases in systemic therapy side effects were seen, occurring at cycle two and continuing over the subsequent assessments. This became a large clinically meaningful effect in the AT arm at the last cycle. Despite this increase, in at least some treatment-related and other problems, global QOL was maintained and showed no or little change during the entire study.
The remaining 14 scales were examined on an exploratory basis and showed no significant differences between the two groups (data not presented). However, in several scales, a clear time effect was observed (Fig 4). In both groups, clinically significant moderate improvements from baseline over treatment were seen in emotional functioning over time (statistically: P < .0001). Also, both groups showed a significant time effect for pain (P = .0014), with clinically small decreases in pain over cycles 2 and 4 in the AT arm and, in the AC arm, a small reduction at cycle 2 and then clinically significant moderate improvement from cycle 4 onwards. In both groups, a statistically significant time effect was seen for role (P = .0014) and physical functioning (P = .0002).
In the AT arm, there seems to be a clinically relevant moderate reduction in both role and physical functioning from cycle two. The remaining scales showed either no changes or limited changes over time.
Bias
Progression Differences in baseline scores were examined between those patients who progressed and those without progression, stratified by treatment, over five key end points. No statistically significant differences were found. In addition, baseline scores were comparable between patients who did or did not drop out. Of the 219 patients with baseline questionnaires, only 121 (55%) completed their questionnaires at all scheduled time points before death or progression.
Drop Out
Prognostic Factor
Using the median score from the EORTC Reference Values manual28 as a cutoff point, scores above and below were compared (Table 4). Using these arbitrary reference levels, HRQOL scores were significantly predictive of survival. With fatigue, for example, it is striking that those women who scored below 40 had a median survival of 25.2 months compared with those with scores above 40 whose median survival was only 18.2 months. The same pattern, although less striking, was seen for the remaining three HRQOL variables.
HRQOL is important for women with metastatic breast cancer for whom treatment is effectively palliative and where it is reasonable to expect that HRQOL deteriorates over time. Chemotherapy may help by maintaining HRQOL over this time. The aim of our trial was therefore to understand the short-term HRQOL of metastatic breast patients when undergoing either AC or AT chemotherapy regimens. Five key scales were selected a priori to avoid type I errors. On these selected scales, no statistical significant difference between the two treatment arms is evident. When compared with large normative, noncancer population data (N = 3,069) reported by Michelson et al,29 women in the current trial had significant impairment of HRQOL of many domains at baseline. We examined baseline HRQOL scores for both groups, finding they were similar before treatment and comparable with scores obtained from the reference values data of other patients from clinical trials.28 This suggests that our population of women are representative of broader groups of women with metastatic breast cancer. In general, we found that over time, HRQOL was impaired in both groups in relation to systemic therapy side effects. That is, patients reported more headaches, feeling unwell, experiencing problems with a dry mouth, and food tasting unusual. These are recognized side effects of chemotherapy, which increased during treatment, and became large clinically meaningful effects in the AT arm. Also in the AT arm, clinically significant moderate increases in fatigue over the course of treatment were seen from baseline. This may suggest that AT treatment may have an important impact on levels of fatigue in these patients. A transient increase in nausea and vomiting was seen at the second cycle in both groups and then returned to scores comparable with baseline levels. Yet the majority of patients presented with low scores for nausea and vomiting, suggesting this caused them only limited difficulties. Alternatively, it is possible that the timing of assessment, which was planned to cause as little inconvenience to patients as possible, did not detect these experiences optimally. The issue of the item "upset by hair loss" was more problematic, and scores stayed relatively the same in both groups over treatment. However, most patients did not experience hair loss problems at baseline and therefore did not answer this item at baseline, as they deemed the question not applicable. Thus the resulting missing data impaired the analysis of this end point. The remaining 14 scales were examined on an exploratory basis. Emotional functioning suggested a significant moderate benefit from both treatments over baseline scores. This improvement was consistent during the treatment period. In addition, although a small clinical improvement was seen in the pain scores of women in the AT arm during cycle 2 and 4, we saw a clinically moderate improvement in the AC arm over baseline at the fourth and sixth cycle. It may be possible that such reductions in pain are a positive result of chemotherapy on the disease. Overall, however, there was no clear difference between the two treatment groups on any HRQOL scale. This is probably because the two treatments had the same clinical efficacy and similar toxicities. Given that the AT arm was characterized by a higher incidence of febrile neutropenia (32% v 9% in the AC arm), we might have expected this to impact more HRQOL, but this seems not to be the case. Indeed, although the sample size is small and statistical power limited, overall assessments for all five key scales in the AT patient group with febrile neutropenia (n = 31) showed no significant difference when compared with the group of those who did not experience febrile neutropenia. However, this small sample gives large CIs, and differences were difficult to detect on the available measures. It is, however, noteworthy that in the AT arm there was a clinically small to borderline moderate reduction in role and physical functioning during treatment when compared with baseline scores.
Another recently published phase III trial incorporating HRQOL18 showed improved median survival of 8.3 months for patients with metastatic breast cancer given first-line treatment with AT compared with 6.2 months for those receiving fluorouracil, doxorubicin, and cyclophosphamide.18 However, HRQOL studies showed no significant difference between treatment arms for eight of 10 functional scales and eight of 13 symptom scales. Where differences were found, these generally favored the regimen of fluorouracil, doxorubicin, and cyclophosphamide and reflected the greater toxicity of AT. Such differences were not seen in the present trial where the level of significance was set at less than .001, as opposed to the level of The problem of poor compliance is common in HRQOL studies in metastatic breast cancer, to such a degree that in some studies, the planned analysis could not be undertaken.3 In the present trial, baseline compliance was comparable to the baseline of 77% to 81% achieved by Jassem et al.18 By comparison, baseline compliance was only 64% in studies of paclitaxel versus doxorubicin6 and of chemotherapy with or without medroxyprogesterone acetate31 in women with advanced breast cancer. Compliance overall was 66%, and because of low compliance (27%) off treatment at 3 months, we were not able to use these data in the analysis. However, our sensitivity analysis supported the main findings, but it was evident that an institutional effect occurred in this trial. This suggests that certain centers had more success in ensuring that patients completed their HRQOL measures. This perhaps is partly expected as the more motivated centers may well invest more resources into the collection of HRQOL data.
We have confirmed that HRQOL scales may predict outcomes for women with breast cancer. Using prognostic factor analysis, baseline scores for all four of the preselected HRQOL scales were significantly predictive of survival (P In conclusion, this study suggests that both AT and AC lead to an initial, statistically significant, and clinically meaningful increase in systemic therapy side effects. This was a large effect in the AT arm, with also increased fatigue levels experienced by patients over baseline scores. However, these effects did not adversely influence global QOL scores, which were maintained and remained consistently stable. Emotional functioning also improved during treatment in both groups. Exploratory analysis also suggests an initial reduction in pain in both groups, with a sustained moderate reduction in pain over all the time points for the AC arm. HRQOL information clearly supplements conventional traditional clinical trial data, and may help both clinicians and patients understand the positive and negative impact of chemotherapy.
The following investigators and their institutions also participated in the study: B. Rapoport, The Medical Oncology Center, Johannesburg, South Africa; M. Nooij, Leiden University Medical Centre, Leiden, The Netherlands; P. Ellis, Guy's Hospital, London, United Kingdom; A. Sulkes, Beilinson Medical Center, Petach Tikva, Israel; H. Curé, Centre Jean Perrin, Clermont Ferrand, France; C. Mendiola, Hospital Universitario 12 de Octubre, Madrid, Spain; D. Spaeth, Centre Alexis Vautrin, Vandoeuvre-les-Nancy, France; R. Morant, Kantonsspital, St Gallen, Switzerland; J.P. Guastalla, Centre Léon Bérard, Lyon, France; C. Dittrich, Kaiser Franz Josef-Spital, Vienna, Austria; L. Beex, Universitair Ziekenhuis Nijmegen, Nijmegen, The Netherlands; L. Mauriac, Fondation Bergonié, Bordeaux, France; K.J. Roozendaal, Onze Lieve Vrouw Gasthuis, Amsterdam, The Netherlands; T. Velu, Hôpital Erasme, Brussels, Belgium; and M. Aapro, European Institute of Oncology, Milan, Italy.
The authors indicated no potential conflicts of interest.
We thank the women who participated in this study. We also thank Irene Van Hoorebeeck for her assistance and all investigators who enrolled trial patients. We also thank Alexander de Graeff and Sheila Sanderson and for their review of the manuscript.
Supported by the Camilla Samuel Fellowship in Memory of Lady Grierson (F.E.). This trial was supported by Bristol-Myers Squibb, Waterloo, Belgium. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 points on a functional scale would mean a moderate improvement, whereas a decrease by 
.05 set by Jassem et al
