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Bisphosphonates and Long-term Survival in Breast Cancer
Abstract & Commentary
By William B. Ershler, MD
Synopsis: The role of bisphosphonates in the treatment and prevention of bone metastases remains incompletely characterized. In the current report, Diel et al detail long-term survival data on patients with known microscopic bone disease more than eight years after adjuvant treatment with clodronate. Although other favorable markers such as reduced bone metastases and disease-free survival, present at earlier analyses, were no longer evident, those who were treated with clodronate continued to have improved overall survival.
Source: Diel IJ, et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol. 2008;19:2007-2011.
Bisphosphonates, administered either orally or intravenously, are known to accumulate within the bone microenvironment and inhibit osteoclast activity. Furthermore, it has been speculated that drugs in this class inhibit tumor cell adhesion to bone and enhance tumor cell apoptosis.1,2 Because of these potential beneficial effects, bisphosphonates have been evaluated for the treatment and prevention of bone metastases in women with breast cancer.3 Early results indicate that adding oral clodronate (Ostac®, Boehringer Mannheim/Roche) to postoperative adjuvant breast cancer therapy significantly improves disease-free survival (DFS) and overall survival (OS).4 In the current report, long-term follow-up data from a prospective, randomized, controlled study are reported.
Primary breast cancer patients were enrolled in the study conducted at the University of Heidelberg between 1990 and 1995. Patients (n = 302) with immunocytochemical evidence of at least one tumor cell per million cells in the bone marrow, but without confirmed distant metastases, including to the bone, were randomized to receive either clodronate 1600 mg/day for two years (treatment group) or standard follow-up (control group). All patients in both groups received standard surgical treatment and customary adjuvant endocrine therapy or chemotherapy with or without radiotherapy. Follow-up evaluations were carried out every 3-4 months during the two-year treatment period.
The current analysis includes a total of 290 of the original 302 patients after a median time of 103 ± 12 months. Earlier reports from this cohort described differences in the incidence of bone and visceral metastases and disease-free survival in the clodronate group (at 36 months  and 55 months ), but these differences were no longer significant at 103 months. However, the significant improvement in overall survival for those in the clodronate group was maintained, with death occurring in 20.4% of the clodronate-treated patients and 40.7% of controls (p = 0.049).
Other studies have examined the role of bisphosphonate treatment in breast cancer. A study by Powles et al6 in which patients with stage I-III breast cancer received oral clodronate or placebo for two years reported better overall survival in the treatment group. In this study, patients were not required to have evidence of tumor cells within the bone marrow. However, they showed that those at highest risk of recurrence experienced the greatest benefit from adjuvant bisphosphonate therapy. In contrast, Saarto et al reported increased bone metastases and reduced survival in clodronate-treated breast cancer patients at both 57 and 10 years8 of follow-up. There were, however, methodological concerns in that study, including imbalanced randomization with more hormone-negative patients in the treatment arm and a fairly large number of protocol violations.
Currently, several trials9 of adjuvant bisphosphonate treatment in patients with breast cancer are recruiting, or have completed patient recruitment, and await data analysis. A study conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP B34) has recruited more than 3,000 patients with primary stages I and II breast cancer to compare the efficacy of oral clodronate with or without chemotherapy and/or hormone therapy in the prevention of bone metastases. The Southwest Oncology Group study (SWOG) is actively recruiting patients (expected accrual of 6,000 patients) to compare the efficacy of oral clodronate, ibandronate, and zoledronic acid in preventing bone metastases in patients who have undergone surgery for stages I-III breast cancer. And, the UK AZURE trial, which has recruited 3,356 patients, was designed to determine whether adjuvant treatment with zoledronic acid plus (neo)adjuvant chemotherapy and/or (neo)adjuvant endocrine therapy is superior to (neo)adjuvant chemotherapy and/or (neo)adjuvant endocrine therapy alone in improving the DFS and bone metastasis-free survival of patients with stages II and III breast cancer. Furthermore, the longer intervals of treatment in the AZURE trial may indicate whether a normalization of bone metabolism leads to a reduction of bone metastases and whether an intravenous application is as effective as an oral one.
Thus, the long-term data presented in the current report suggest an active role for bisphosphonates administered in the adjuvant setting for women with breast cancer. Hopefully, the larger trials will provide the needed data from which clinicians may be guided regarding which patients to treat and for how long.
1. Mundy G. Preclinical models of bone metastases. Semin Oncol. 2001;28:2-8.
2. Yoneda T, et al. Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma. Cancer. 2000;88:2979-2988.
3. Gnant M, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol. 2008;9: 840-849.
4. Diel IJ, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med. 1998;339:357-363.
5. Diel IJ. Bisphosphonates in the prevention of bone metastases: current evidence. Semin Oncol. 2001;28: 75-80.
6. Powles T, et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol. 2002;20:3219-3224.
7. Saarto T, et al. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol. 2001;19:10-17.
8. Saarto T, et al. Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol. 2004;43:650-656.