Systemic Therapy for Bone Metastases
Data from multiple studies suggest that bisphosphonates may directly or indirectly impair multiple processes required for cancer growth and metastases. Bisphosphonates have demonstrated an ability to induce apoptosis in a variety of cancer cell lines. These agents may also inhibit metastases by decreasing tumor cell adhesion, migration, and invasion. Inhibition of angiogenesis is another property associated with bisphosphonates. Furthermore, these pharmacologic agents may modulate the immune system with subsequent antitumor activity. Recent research also found that zoledronic acid may exert its antitumor activity by inhibiting mesenchymal stem cell migration and blocking mesenchymal stem cell secretion of factors involved in breast cancer progression.
In the clinical setting, a potential preventive effect of bisphosphonates was reported in a retrospective analysis of women with osteoporosis who participated in the Women's Health Initiative Observational Study. Women who received bisphosphonates had a 32% relative reduction (P < .01) in the risk of breast cancer compared with women without this therapy. Similar results were observed in the Breast Cancer in Northern Israel Study, with a 28% reduced risk of breast cancer in postmenopausal women who received bisphosphonates for more than 1 year. Further, a recent investigation determined that the use of oral bisphosphonates for more than 1 year was associated with a 59% relative reduction in the risk of colorectal cancer.
A meta-analysis of clinical trials from 1966 to 2006 compared patients with breast cancer who received up to 3 years of clodronate with patients who did not receive this medication. There were no significant benefits for patients taking clodronate in regard to overall survival, bone metastases-free survival, or nonskeletal metastases-free survival. The Austrian Breast and Colorectal Cancer Study Group trial (ABCSG-12) tested the effect of adding zoledronic acid every 6 months for 3 years to adjuvant endocrine therapy with tamoxifen and goserelin or anastrozole and goserelin in premenopausal patients with hormone receptor-positive earlystage breast cancer. The addition of zoledronic acid provided a relative 36% reduction in the risk of disease progression (P = .01). A recent 62-month follow-up of this study reported a persistent relative 32% benefit in disease-free survival for the patients who received zoledronic acid (P = .009).
The Zometa-Femara Adjuvant Synergy trials (Z-FAST/ZO-FAST/E-ZO-FAST) compared immediate vs delayed zoledronic acid in postmenopausal women with earlystage breast cancer who received adjuvant letrozole. The Z-FAST trial determined a 20% relative reduction in risk of disease recurrence for the immediate-treated zoledronic acid group. The ZO-FAST study found a 41% relative decrease in disease recurrence. However, conflicting results were reported for the E-ZO-FAST trial (N = 527), with 19 vs 11 recurrences in the immediate and delayed arms, respectively (hazard ratio [HR] = 1.76; 95% confidence interval [CI] = 0.83, 3.69).
Another investigation determined that current bisphosphonate use, especially with alendronate, was associated with a substantial 59% reduction in the risk of contralateral breast cancer in patients with estrogen receptor-positive breast cancer. The risk of contralateral breast cancer declined further with longer duration of bisphosphonate use. However, recent results from the AZURE trial failed to demonstrate an overall benefit for the addition of zoledronic acid to adjuvant chemotherapy or endocrine therapy in patients with breast cancer. Definitive recommendations for the use of bisphosphonates in the adjuvant setting will require further study and follow-up data.
The issue of potential risk of esophageal cancer with oral bisphosphonate use was raised from data from the FDA and the United Kingdom. However, other investigations from the United Kingdom and Denmark have not found any association between the development of esophageal cancer and oral bisphosphonate use. The FDA recently announced plans to continue review of the conflicting studies.
Potential Antitumor Effects of Bisphosphonates
Data from multiple studies suggest that bisphosphonates may directly or indirectly impair multiple processes required for cancer growth and metastases. Bisphosphonates have demonstrated an ability to induce apoptosis in a variety of cancer cell lines. These agents may also inhibit metastases by decreasing tumor cell adhesion, migration, and invasion. Inhibition of angiogenesis is another property associated with bisphosphonates. Furthermore, these pharmacologic agents may modulate the immune system with subsequent antitumor activity. Recent research also found that zoledronic acid may exert its antitumor activity by inhibiting mesenchymal stem cell migration and blocking mesenchymal stem cell secretion of factors involved in breast cancer progression.
In the clinical setting, a potential preventive effect of bisphosphonates was reported in a retrospective analysis of women with osteoporosis who participated in the Women's Health Initiative Observational Study. Women who received bisphosphonates had a 32% relative reduction (P < .01) in the risk of breast cancer compared with women without this therapy. Similar results were observed in the Breast Cancer in Northern Israel Study, with a 28% reduced risk of breast cancer in postmenopausal women who received bisphosphonates for more than 1 year. Further, a recent investigation determined that the use of oral bisphosphonates for more than 1 year was associated with a 59% relative reduction in the risk of colorectal cancer.
A meta-analysis of clinical trials from 1966 to 2006 compared patients with breast cancer who received up to 3 years of clodronate with patients who did not receive this medication. There were no significant benefits for patients taking clodronate in regard to overall survival, bone metastases-free survival, or nonskeletal metastases-free survival. The Austrian Breast and Colorectal Cancer Study Group trial (ABCSG-12) tested the effect of adding zoledronic acid every 6 months for 3 years to adjuvant endocrine therapy with tamoxifen and goserelin or anastrozole and goserelin in premenopausal patients with hormone receptor-positive earlystage breast cancer. The addition of zoledronic acid provided a relative 36% reduction in the risk of disease progression (P = .01). A recent 62-month follow-up of this study reported a persistent relative 32% benefit in disease-free survival for the patients who received zoledronic acid (P = .009).
The Zometa-Femara Adjuvant Synergy trials (Z-FAST/ZO-FAST/E-ZO-FAST) compared immediate vs delayed zoledronic acid in postmenopausal women with earlystage breast cancer who received adjuvant letrozole. The Z-FAST trial determined a 20% relative reduction in risk of disease recurrence for the immediate-treated zoledronic acid group. The ZO-FAST study found a 41% relative decrease in disease recurrence. However, conflicting results were reported for the E-ZO-FAST trial (N = 527), with 19 vs 11 recurrences in the immediate and delayed arms, respectively (hazard ratio [HR] = 1.76; 95% confidence interval [CI] = 0.83, 3.69).
Another investigation determined that current bisphosphonate use, especially with alendronate, was associated with a substantial 59% reduction in the risk of contralateral breast cancer in patients with estrogen receptor-positive breast cancer. The risk of contralateral breast cancer declined further with longer duration of bisphosphonate use. However, recent results from the AZURE trial failed to demonstrate an overall benefit for the addition of zoledronic acid to adjuvant chemotherapy or endocrine therapy in patients with breast cancer. Definitive recommendations for the use of bisphosphonates in the adjuvant setting will require further study and follow-up data.
The issue of potential risk of esophageal cancer with oral bisphosphonate use was raised from data from the FDA and the United Kingdom. However, other investigations from the United Kingdom and Denmark have not found any association between the development of esophageal cancer and oral bisphosphonate use. The FDA recently announced plans to continue review of the conflicting studies.
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