Abstract
Background: The current study aimed to examine the impact of zoledronic acid therapy on health-related quality of life (HRQoL) in Taiwanese patients with bone metastases from breast cancer. Patients and Methods: Patients with bone metastases from breast cancer who received zoledronic acid according to the standards of care were enrolled in this observational phase IV study. HRQoL was measured monthly using the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (QLQ-C30) and the breast cancer-specific module (BR-23) for 24 months. Results: A total of 366 patients from 13 centers were enrolled. QLQ C-30 demonstrated that zoledronic acid improved the HRQoL in different aspects. In particular, a significant reduction of pain in the first 14 months and the 22-month follow-up was reported by patients. QLQ-BR23 indicated improved future perspective and breast symptom scores over the course of the study. Conclusion: These data confirm the HRQoL benefits and safety of zoledronic acid in Taiwanese patients with bone metastases from breast cancer.
Bone metastasis is common during disease progression in patients with advanced breast cancer (1, 2). The majority of patients with bone metastases will subsequently develop irreversible skeletal complications including pathological fracture, spinal cord compression, and a requirement for surgical intervention and palliative radiotherapy to the bone lesion, known collectively as skeletal-related events (SREs). SREs are associated with unfavorable prognosis and cause significant pain and morbidity that negatively affect the patients' quality of life (QoL) (3).
Zoledronic acid is a bisphosphonate, potently inhibiting osteoclast-mediated bone resorption. Its mechanisms of action include inhibition of osteoclast differentiation and maturation, reduced osteoclast activity, and induction of osteoclast apoptosis (4). Zoledronic acid is the standard-of-care for delaying or preventing SRE in metastatic cancer. Zoledronic acid significantly reduced the risk of SRE in patients with breast cancer in randomized, double-blind, placebo-controlled and comparative trials (5, 6).
Currently, advanced cancer such as metastatic breast cancer is mostly considered to be incurable, and the goals of treatment are generally palliative. Because improvement in survival and response to treatment are difficult to achieve in patients with metastatic breast cancer, outcome measures in palliative care for patients with metastatic breast cancer require the measurement of aspects that reflect the patient's sense of well-being or QoL. Patient self-reports of health-related (HR)QoL has become a standard end-point in many clinical trials for diseases such as metastatic breast cancer (7). We conducted a single-arm, multicenter, open-label, observational, phase IV study of zoledronic acid therapy in Taiwanese patients with bone metastases from breast cancer. The primary end-point was to determine the change of scores in two HRQoL questionnaires, Quality of Life Core Questionnaire 30 (QLQ-C30) and the breast cancer-specific module (BR-23), from the European Organization for Research and Treatment of Cancer (EORTC), after the administration of zoledronic acid. The secondary end-point of this study was to assess the safety and tolerability of zoledronic acid during extended administration of 24 months in these patients.
Patients and Methods
Eligibility criteria. This phase IV, single-arm, non-comparative, open label, and prospective study was conducted across 13 centers in Taiwan between July 2008 and November 2012. Patients who received zoledronic acid according to standards of care under the supervision of the treating physician were offered enrollment into this observational study. The criteria for inclusion were female, ≥20 years of age, with histologically- or cytologically-confirmed diagnosis of breast cancer and radiological evidence of one or more bone metastases. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and life expectancy of more than two years. Exclusion criteria were as follows: i) radiotherapy to bone within three months prior to study; ii) serum calcium concentration >2.7 mmol/l or <2.0 mmol/l; iii) abnormal renal function as evidenced by a calculated creatinine clearance <30 ml/min; iv) pregnant or lactating patients, or patients of childbearing potential not implementing adequate contraceptive measures; v) prior treatment with bisphosphonates; vi) evidence of severe cardiovascular disease, refractory hypertension, or symptomatic coronary artery disease within six months prior to study; vii) current active dental problems, or a current or prior diagnosis of osteonecrosis of the jaw; viii) recent (within six weeks) or planned dental or jaw surgery. This study was approved by the Institutional Review Board of all thirteen medical centers, and written informed consent was obtained from all patients.
Study design and end-point assessment. The objective of this prospective, non-intervention, observational study was to assess the overall HRQoL and provide additional data to confirm the safety profile of zoledronic acid for Taiwanese patients with bone metastases from breast cancer treated in clinical practice for up to 24 months. As a standard-of-care, patients received 4 mg of zoledronic acid via 15-min intravenous infusion every month. The dose of zoledronic acid was reduced in the presence of renal dysfunction to prevent unacceptable toxicity, as indicated by calculated creatinine clearance of <60 ml/min.
Summary of patients' demographics and characteristics (N=366).
The primary end-point was measured by evaluating HRQoL using EORTC QLQ-C30 and BR23 questionnaires. The EORTC QLQ-C30 questionnaire composes of a two-item global health and QoL scale, five multi-item functional scales (physical, role, emotional, cognitive, and social), and three multi-item (fatigue, pain, and nausea/vomiting) and six single-item (dyspnea, insomnia, appetite, constipation, diarrhea, and financial impact) symptom scales. The BR23 comprises of 23 breast cancer-specific items that include four functional (body image, future perspective, sexual functioning and enjoyment) and four symptom (systemic therapy side effects, upset by hair loss, breast and arm symptoms) scales.
We also assessed the safety and tolerability of zoledronic acid during a 24-month treatment period in these patients. The assessment of safety was carried out by recording all adverse events (AEs), which included drug-related AEs, SRE, and monitoring of renal function by calculated creatinine clearance.
Statistical analysis. Analysis was performed based on results collected as of June 2012. The scoring of the QLQ-C30 and BR23 items were performed as previously described (8). A change of score from baseline of more than 10% was considered clinically significant. The changes in the QoL scores from baseline at each evaluation point were analyzed by longitudinal data with mixed model. All statistical analyses were carried out using a two-sided test at the 0.05 level of significance.
Mean±standard error (EORTC QLQ-C30) sub-scale scores from time of baseline to different time-points.
Mean±standard error (EORTC QLQ-BR23) subscale scores from time of baseline to different time-points.
Results
HRQoL assessment. A total of 366 patients from 13 centers were enrolled in this study. Of the 366 patients, 153 (41.8%) completed baseline and all follow-up questionnaires up to the 24th month. Two hundred and thirteen (58.2%) failed to complete the questionnaires up to the 24th month; 69 patients (18.9%) died during the study period, 95 (26.0%) withdrew their consent, 12 (3.3%) terminated the study prematurely due to AEs, 25 (6.8%) discontinued study medication, 10 (2.7%) were lost to follow-up and two patients (0.5%) dropped out from the study due to abnormal laboratory results. The demographic characteristics of the patients are summarized in Table I. The average follow-up period per patient was 15.3 months.
Table II provides the bi-monthly global QoL, functional and symptom scores of patients as measured by EORTC QLQ-30. Global QoL score increased slightly and functioning scores fluctuated throughout the study period, with no significant change noted. Assessment of patient perception of symptoms revealed significant reduction of nausea and vomiting (at 20- and 22-month follow-up), pain (from 2- to 12-month and 22-month follow-up), insomnia (from 6- to 20-month follow-up), appetite loss (at 16-month follow-up), constipation (at 8-, 10-, 18-, and 22-month follow-up), diarrhea (at 20- and 22-month follow-up) and financial difficulties (at 2- and 4-month follow-up).
HRQoL scores as measured by the BR23 breast cancer module are shown in Table III. Over the course of the study, patients reported significant improvements in future perspectives compared with baseline. Breast symptoms showed significant reduction at 4-month and from 8-month to 24-month follow-up. Body image, sexual functioning, arm symptoms, upset by hair loss, and systemic therapy side-effects remained stable, with no significant changes reported. Only a significant decrease of sexual enjoyment was observed at 4-month follow-up compared to the baseline assessment.
Safety assessment. A total of 347 patients (94.8%) reported at least one AE during the study period; 53 patients (14.5%) reported AEs that were classified as being drug-related by investigators. The most frequently occurring drug-related AEs (incidence greater than 1%) are summarized in Table IV. SREs were encountered in 58 patients (15.8%), including radiation to bone (49 patients, 13.4%), surgery to bone (7 patients, 1.9%), pathological fracture (6 patients, 1.6%), and spinal cord compression (3 patient, 0.8%).
Discussion
Patients with bone metastases are at high risk for developing SREs (3, 9). Previous reports have shown that without treatment, approximately 70% of patients with bone metastases from breast cancer will experience repeated SREs within two years, which can lead to a significant reduction in patients' QoL (10, 11). Zoledronic acid significantly reduces the incidence of SREs, delays the first SRE, reduces the need for radiotherapy, and averts bone pain in randomized placebo-controlled trials and is currently standard for the prevention of SREs in patients with bone metastases from breast cancer (9, 12). By preventing SREs, zoledronic acid has been shown to positively impact QoL (13).
Drug-related adverse events with incidence greater than 1% in 366 patients with bone metastases from breast cancer.
This prospective, non-comparative, non-intervention, observational phase IV study evaluated the HRQoL in Taiwanese patients with bone metastases from breast cancer receiving zoledronic acid treatment. The EORTC QLQ-30, which emphasizes on the patient's ability to fulfill activities of daily living, in conjunction with the breast cancer-specific module EORTC QLQ-BR23 were used to assess the potential HRQoL benefit of zoledronic acid therapy. Our QLQ-30 scores revealed that all functional scores fluctuated throughout the 24-month follow-up, with no significant changes in this cohort of Taiwanese patients with advanced breast cancer. Previous studies examining the therapeutic effects of zoledronic acid in patients with bone metastases from breast cancer have demonstrated significant reduction in pain (5, 14). Notably, pain scores decreased from baseline at all points during a 12-month study in a randomized, placebo-controlled trial (5). In agreement, our results showed the analgesic effect of zoledronic acid, in which significantly improved pain scores versus those at baseline were reported by patients within the first 14 months and at the 22-month follow-up of the study period. The QLQ-30 symptom sub-scale scores also indicated a significant reduction of vomiting (at 20- and 22-month follow-up), insomnia (from 6- to 20-month follow-up), appetite loss (at 16-month follow-up), constipation (at 8-, 10-, 18-, and 22-month follow-up), diarrhea (at 20- and 22-month follow-up) and financial difficulties (at 2- and 4-month follow-up).
According to our findings obtained by the QLQ-BR23 breast cancer-specific questionnaire, breast symptoms and future perspective scores improved significantly over the course of the study. Body image, sexual functioning, arm symptoms, upset by hair loss, and systemic therapy side-effects sub-scales remained stable. A significantly reduced sexual enjoyment score was reported by patients. Previous studies have suggested sexual dysfunction to be a result of premature menopause after adjuvant systemic therapy in patients with breast cancer (15, 16).
In the present study, zoledronic acid was well-tolerated, with safety profiles within the expected. The incidence of SREs (15.8%) was considerably lower than previously reported (5, 17). In these reports, about 30% of patients who received zoledronic acid experienced an SRE during the 12-month period. We believe that this difference may be at least partly attributable to the varying degree of disease severity of the enrolled patients. In our study, a higher percentage of patients had an ECOG performance status score <2 (94.0% versus 88.6% and 87.2%). Osteonecrosis of the jaw was a rare but serious complication in relation to treatment with bisphosphonates. The incidence of jaw osteonecrosis in this study (1.4%) was low and similar to previous reports on zoledronic acid (18, 19).
Effective management of advanced breast cancer must include specific goals in palliative care, such as improving the QoL. This prospective study confirmed and extended previous findings demonstrating that zoledronic acid is safe and improves bone metastasis-related symptoms and important aspects of QOL in Taiwanese patients with breast cancer.
Acknowledgements
This work was supported by Novartis (Taiwan) Co., Ltd.
Footnotes
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This article is freely accessible online.
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Declaration of Interests
The Authors have declared that no competing interests exist.
- Received October 15, 2013.
- Revision received November 6, 2013.
- Accepted November 7, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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