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© 2002 American Society for Clinical Oncology Effects on Quality of Life of Combined Trastuzumab and Chemotherapy in Women With Metastatic Breast CancerByFrom Quality of Life Consulting, West Vancouver, British Columbia, Canada; The Herceptin Multinational Investigator Group, Division of Hematology/Oncology, University of California Los Angeles School of Medicine, Los Angeles; and Genentech Incorporated, South San Francisco, CA. Address reprint requests to D. Osoba, MD, Quality of Life Consulting, 4939 Edendale Ct, West Vancouver, British Columbia, Canada V7W 3H7; email: david_osoba{at}telus.net
PURPOSE: The study was designed to compare the effects of treatment with a combination of trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) and chemotherapy versus chemotherapy alone on health-related quality of life (HRQL) in patients with HER-2/neu overexpressing, metastatic breast cancer.
PATIENTS AND METHODS: A sample of 400 patients, not previously treated for metastatic disease and randomized to receive either trastuzumab plus chemotherapy (208 patients) or chemotherapy alone (192 patients), completed the European Organization for Research and Treatment Care Quality of Life Questionnaire at baseline and on at least one subsequent occasion at 8, 20, 32, 44, and 56 weeks. HRQL improvement or worsening was defined as a RESULTS: After completion of chemotherapy, patients treated with trastuzumab and chemotherapy reported significant improvement in fatigue (P < .05) as compared with their baseline scores. Higher proportions of patients receiving the combined therapy achieved improvement in global QOL (P < .05) than did patients treated with chemotherapy alone. Higher proportions of the combined therapy group also achieved improvement in physical and role functioning and in fatigue as compared with the chemotherapy group, but the differences were not statistically significant. There were no differences in the proportions of patients in the two groups that reported worsening. CONCLUSION: Statistically significantly higher proportions of patients treated with a combination of trastuzumab and chemotherapy reported improved global QOL than did patients treated by chemotherapy alone.
THE RECENT INTRODUCTION of a recombinant, humanized, monoclonal antibody (trastuzumab [Herceptin, Genentech, Inc, South San Francisco, CA]) for the treatment of HER-2/neu overexpressing, metastatic breast cancer represents a new form of therapy for this disease.1-4 Although HER-2/neu is overexpressed in only approximately 20% to 30% of women with breast cancer, the disease is more likely to progress and is more resistant to chemotherapy than is HER-2/neu negative disease.5-9 Preclinical and early clinical studies have shown that the efficacy of trastuzumab is greatly enhanced when combined with chemotherapy.10-15 These findings led to a randomized, controlled, phase III trial in which patients with HER-2/neu overexpressing breast cancer and who had not had previous chemotherapy for metastatic disease were given either trastuzumab combined with doxorubicin/epirubicin and cyclophosphamide (if they had no adjuvant chemotherapy with these drugs) or with paclitaxel (if they had received an anthracycline during adjuvant treatment).4 The combination of trastuzumab with chemotherapy improved objective response rates and significantly prolonged median time to disease progression, median duration of response, and survival as compared with treatment with chemotherapy alone. These benefits were evident despite the cross-over design of the study, which resulted in 66% of patients initially randomized to chemotherapy alone subsequently also receiving trastuzumab and despite the development of cardiac dysfunction (New York Heart Association class III/IV) in 18% of patients receiving trastuzumab and chemotherapy.4 Although modest prolongation of survival often is achieved in metastatic cancer, there is still no long-term decrease in mortality.16-19 In this situation, the measurement of health-related quality of life (HRQL) provides additional data for evaluating the effect of treatment. Ideally, any gain in survival also should be accompanied by an improvement in HRQL or at least stable HRQL if the therapy is to be judged as being worthwhile. However, increased survival with deterioration in HRQL should raise questions about the value of the therapy being tested. In addition, when a new treatment is introduced for the therapy of cancer, and its effects on the disease and its toxicity are not fully known, HRQL should be measured to obtain as much information as possible about how the new therapy affects patients’ well-being. Accordingly, HRQL was measured as a component of the study cited above.4 This report deals with the results obtained in a sample of 400 women (of 469 entered onto the clinical efficacy study). The working hypothesis, stated a priori and tested in preliminary analyses,20 was that there would be no difference between the two groups with respect to HRQL outcomes. Six domains (scales) of the European Organization for Research and Treatment of Cancer core Quality of Life Questionnaire (EORTC QLQ-C30) were prospectively chosen as the primary variables of interest. These were global quality of life (QOL), physical, role, social, and emotional functioning, and fatigue. Within these domains are the three major dimensions of health included in the World Health Organization’s definition of health,21 and in addition, fatigue is an important symptom often experienced by women with breast cancer.22-24
Patients Eligible patients had to have progressive, metastatic breast cancer with overexpression of the HER-2/neu oncogene, bi-dimensionally measurable disease (excluding osteoblastic metastasis, pleural effusions, or ascites), not been previously treated with chemotherapy for metastatic disease, 18 years or older, and capable of receiving concomitant cytotoxic chemotherapy. Exclusion criteria included previous cytotoxic chemotherapy for metastatic breast cancer, concomitant malignancy that had not been curatively treated, Karnofsky performance status of less than 60, and clinically unstable or untreated metastasis to the brain. Full details of eligibility criteria have been presented elsewhere.4 All patients signed a written consent form. Eligible, consenting women were randomized to receive chemotherapy with or without trastuzumab. The chemotherapy regimen for both treatment groups was either anthracycline (doxorubicin 60 mg/m2 or epirubicin 75 mg/m2 as a slow intravenous [IV] push) plus cyclophosphamide (600 mg/m2) or paclitaxel (75 mg/m2 over 3 hours by IV infusion). Patients who had not received anthracycline therapy in the adjuvant setting were stratified to receive anthracycline, whereas those who had received any anthracycline therapy in the adjuvant setting were stratified to receive paclitaxel. Patients randomized to receive trastuzumab were given 4 mg/kg as an IV loading dose and then 2 mg/kg every week as an IV infusion for 30 to 90 minutes. The initial loading dose preceded chemotherapy by 24 hours, and subsequent doses were given immediately before chemotherapy on the same day. The treatment was repeated every 3 weeks for an intended total of six cycles unless patients experienced intolerable toxicity or the disease progressed. After disease progression, those who had been randomized to receive chemotherapy alone could choose to receive trastuzumab alone or in combination with other therapies in an open-label extension study. Those who had completed six cycles of trastuzumab and chemotherapy and did not have disease progression could continue on this treatment at the investigator’s discretion. This treatment design resulted in four treatment subgroups of patients: (1) trastuzumab plus either doxorubicin or epirubicin, (2) doxorubicin or epirubicin only, (3) trastuzumab plus paclitaxel, and (4) paclitaxel only. For most of the analyses of QOL data, the four treatment groups were aggregated into two groups that were trastuzumab plus chemotherapy and chemotherapy alone (see below).
HRQL Assessment and Analysis The HRQL assessments in all groups of patients were scheduled at baseline (within 2 weeks before the initiation of therapy) and subsequently at weeks 8, 20, and every 12 weeks thereafter until disease progression, intolerable toxicity, or patient refusal to complete more questionnaires. All assessments were to be completed in the clinic before the administration of the treatment. The QLQ-C30 responses were scored and analyzed according to algorithms in a scoring manual supplied by the EORTC Study Group on Quality of Life.27 All raw scores were transformed to a 0 to 100 scale. For the functioning scales and the global QOL scale, higher scores indicate better functioning, whereas in the symptom scales and items, higher scores indicate more problems with the symptom. A psychometric analysis of the QLQ-C30 was carried out in this sample to assess the properties of the instrument in this population. Internal consistency estimates (Cronbach’s alpha coefficient) for the six selected domains were similar to those previously reported for women with metastatic breast cancer26 and patients with lung cancer.25 Cronbach’s alphas were as follows for each domain: physical functioning, 0.75; role functioning, 0.57; emotional functioning, 0.75; social functioning, 0.86; global QOL, 0.90; and fatigue, 0.88. Mean baseline scores for the six domains were also similar to those previously reported in women with metastatic breast cancer.26 Follow-up questionnaire completions were assigned for analysis based on the following windows of time: week 8 (weeks 3 to 14), week 20 (weeks 15 to 25), week 32 (weeks 26 to 38), week 44 (weeks 39 to 50), and week 56 (weeks 51 to 62). These windows were chosen so that all the data could be included even if treatment may have been delayed for 1 or 2 weeks. In actual fact, almost all (more than 90%) questionnaire completions were within 2 weeks of the specified completion time, and there were no differences between treatment arms. Follow-up HRQL information after discontinuation from the study was not used in the analysis because of the paucity of data. The numbers of patients in each analysis may differ from scale to scale because some patients may have had randomly missing scores on certain scales. HRQL analyses were based on the patients’ original treatment assignment. Two types of analyses were carried out using a SAS statistical program (SAS Institute, Cary, NC).28 In the first, the change in scores from baseline to any given time during the study was calculated by subtracting the baseline score for each patient from the subsequent scores for the same patient. The mean of the changes in scores for all patients at a given time were calculated and compared between the two treatment groups. An increase in scores more than baseline scores for the global QOL and functioning scales indicated improvement, whereas an increase in scores for the fatigue scale indicated worsening of HRQL. The mean of the changes in both treatment groups were compared by a Student’s t test. Changes from baseline between treatment groups were considered as significant at a level of P < .05 after a Bonferroni correction, taking into account the number of comparisons and the average inter-domain correlation for the six domains of interest (0.21).29 This calculation resulted in the exclusion of comparisons that did not reach an alpha level of 0.003 before the Bonferroni correction.
The second analysis involved a calculation of the proportions of patients in each treatment group who reported a subjectively significant change30 (minimal important difference31,32 in each of the six domains during treatment and follow-up as compared with baseline). Based on the results of previous studies in patients with breast cancer,30 a subjectively significant change in QLQ-C30 scores is one that is
The proportions experiencing a subjectively significant change in each treatment group were compared using a
Baseline Characteristics of Subjects Eligible for HRQL Analysis The baseline characteristics and HRQL scores for each group of patients showed no significant differences between the groups with respect to age, race, or Karnofsky Performance Status (Table 1). Baseline HRQL scores for each domain were similar in all treatment groups, with the exception that the score for role functioning varied slightly between the smaller treatment groups. However, when the smaller groups were aggregated into the two major treatment groups, there was no difference between the trastuzumab plus chemotherapy and the chemotherapy alone groups.
Questionnaire Completion Rates Of 469 patients enrolled onto the study, 431 (92%) completed the QLQ-C30 at baseline. The number of patients available for HRQL analysis (ie, those who had a baseline assessment and at least one follow-up assessment) was 400 patients (86% of the total number of enrolled patients and 93% of those who had completed the baseline assessment). The attrition rates of patients who completed baseline and follow-up assessments are provided in Fig 1. When compared with baseline, the proportion of patients completing the QLQ-C30 at each time point up to 56 weeks was much higher in the trastuzumab plus chemotherapy group than in the chemotherapy alone group (panel A). For example, by week 32, 71.6% of patients in the combined therapy arm completed the QLQ-C30, whereas only 46.4% in the chemotherapy alone arm did so. Lack of questionnaire completion was almost entirely because of the development of disease progression and subsequent removal from the study. However, there were no major discrepancies in the proportions of patients completing the questionnaire over the number still on study or in patients expected to complete at each time point (panel B). The proportions varied from 87.3% to 97.4% in both treatment groups until week 56 of the study and then dropped to less than 66%.
The patients who continued longest on the study were more likely to have better mean baseline scores than did the entire group of patients and those who dropped out by 8 weeks. This finding was more striking for those who were treated by chemotherapy alone than for those who received both trastuzumab and chemotherapy. For example, the mean baseline score for global QOL of those treated by chemotherapy alone and still on the study at 44 weeks was 68.2 as compared with 58.5 for the entire treatment group and 60.6 for those who were able to complete only the week 8 assessment. However, for those treated by both trastuzumab and chemotherapy, the analogous mean baseline scores were 63.0 for those at week 44, 59.0 at pretreatment, and 60.4 at week 8. Similarly for role functioning, the difference between the week 44 mean score of 77.5 and the pretreatment mean score of 66.4 is quite large in those treated by chemotherapy alone. The difference is much smaller (68.9 v 65.1, respectively) for those treated by trastuzumab and chemotherapy. These differences were not subjected to statistical analysis because this was an observation made during the study and not based on any a priori hypothesis.
HRQL Changes From Baseline During Treatment and Follow-Up
Proportions of Patients With Subjectively Significant Improvement in HRQL The proportion of patients with improvements of  10 in their HRQL scores as compared with baseline was statistically significantly higher for global QOL in the patients treated with trastuzumab and chemotherapy compared with chemotherapy alone (Fig 3). Fifty-one percent of patients reported an improvement of 10 in their global QOL scores in the combined therapy group as compared with 36% in the chemotherapy alone group (P < .05 after a Bonferroni correction). For the fatigue domain, 52% of patients in the combined therapy group reported an improvement of 10 compared with 42% of patients in the chemotherapy only group, but this difference was not statistically significant. The proportions of patients in the trastuzumab plus chemotherapy group reporting an improvement in physical, role, social, and emotional functioning were also higher than in the chemotherapy alone group, but the differences were not statistically significant (Fig 3).
More patients receiving chemotherapy alone than patients receiving trastuzumab plus chemotherapy reported stable scores in the global QOL (21% v 9%; P < .05 after Bonferroni correction). There were no statistically significant differences between the groups with respect to the proportions of patients reporting worsening of 10 in the scores of any of the HRQL domains.
Our initial hypothesis that there would be no difference in HRQL scores between the treatment groups was stated a priori.20 However, in this study, there were HRQL differences between the patients treated by a combination of trastuzumab and chemotherapy alone as compared with chemotherapy alone. Although HRQL scores were similar at 8 weeks, there was a statistically significant improvement of fatigue in the group treated with trastuzumab plus chemotherapy at 32 weeks. Also, a significantly higher proportion of patients who received the combination had improvement (51% v 36%) in global QOL (P < .05). These statistically significant differences were found after a Bonferroni correction for multiple testing. Whereas the application of this correction is appropriate to reduce the chance of a type I error (that a difference occurred by chance), it increases the chance of a type II error (that a true difference will be missed).29 There is evidence that trastuzumab augments the effects of chemotherapy. In vitro studies have found that cisplatin, carboplatin,10,12 and docetaxel13 were synergistic, whereas doxorubicin, paclitaxel, methotrexate, and cyclophosphamide were additive11-15 with trastuzumab. The phase III clinical trial (from which the HRQL data reported here were collected) showed significant prolongation of survival in patients treated with both trastuzumab and chemotherapy as compared with chemotherapy alone.4 It is expected that HRQL should improve when there is an effective antitumor treatment that results in a decrease of tumor masses in the body, provided that the toxicity of the treatment does not abrogate the benefits of tumor reduction. It would seem, from the results of this study, that the potentially deleterious effects of toxicity on HRQL were noted during early treatment (at 8 weeks) because there were either decreases or no improvement in HRQL scores in both groups. Thereafter, when the initial planned course of treatment had been completed (at 20 weeks and later), fatigue scores in patients receiving chemotherapy alone still remained below or at pretreatment values, whereas they improved significantly more than pretreatment values in those who had received both trastuzumab and chemotherapy. Thus, patients receiving the combined therapy seemed to recover from fatigue, whereas those receiving chemotherapy alone did not show suggestions of recovery until later (56 weeks). By this time, the number of patients remaining in the study was too small to draw conclusions. The reasons for improvement in global QOL and fatigue in those patients who were treated with the combined therapy are likely associated with the decreases in tumor mass. In the main clinical efficacy study, there were significantly higher proportions of patients with objective reductions in tumor, a longer time to disease progression, and a longer maintenance of tumor response (less than 0.001 in each case).4 These patients also survived longer than did those treated with chemotherapy alone. A subgroup of patients (18%) treated with trastuzumab, an anthracycline, and cyclophosphamide developed New York Heart Association class III/IV cardiac toxicity.4 This group was analyzed as a separate group for HRQL effects, but the global QOL scores suggest that any deleterious effects were insufficient to influence the group results (data not shown). A likely explanation is that the cardiac toxicity was treated promptly and was not of sufficient duration for possible HRQL effects to be seen in HRQL assessments performed only every 12 weeks. The finding that patients who were able to continue on the study tended to have higher baseline HRQL scores than did those who dropped out earlier may be of interest. However, statistical analysis of these results was not carried out, and they will need to be tested a priori in future studies. We speculate that pretreatment HRQL status may have prognostic value for remaining progression-free and for length of survival. Others have previously demonstrated a relationship between higher baseline HRQL scores and length of survival in studies of patients with metastatic breast cancer.36-39 It is unknown why self-reported QOL scores are prognostic for survival and, particularly, why they are more accurate than performance status.37 It would seem that patients with metastatic cancer are better judges of their health as expressed in HRQL scores than are performance status scores, physical examination, or laboratory studies. Second, these results also may demonstrate a new finding, which is that the kind of treatment given may have a differential selective effect on survival. Whereas those treated with chemotherapy alone had a better chance of still being available for follow-up if their initial HRQL scores were better, those treated by trastuzumab plus chemotherapy survived equally well regardless of their initial scores. Thus, trastuzumab treatment may have provided an opportunity for patients to survive who might not have done so if treated with chemotherapy alone. This suggests that the addition of trastuzumab to chemotherapy may mitigate the poorer prognosis of lower pretreatment HRQL scores. This possibility needs to be formally tested in a future study. These HRQL findings reported here should be interpreted in the context of the results of the main clinical efficacy study.4 Taken together with the significant improvements in disease response rates, median duration of response, time to disease progression, and in survival, they provide additional support for the benefit of trastuzumab combined with chemotherapy as compared with chemotherapy alone for the treatment of HER-2/neu overexpressing, metastatic breast cancer.
Supported by Genentech Inc, South San Francisco, CA.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. After a Bonferroni correction, taking into account the number of comparisons (18) and the inter-domain correlation (0.21), P values less than .05 were considered to be statistically significant. This calculation resulted in the exclusion of all comparisons in which an alpha level of 0.005 was not reached before the Bonferroni correction. 
