Cancer Treatment Today

The bisphosphonate Zometa is approved for the treatment of hypercalcemia of malignancy, as well as the treatment of documented bone metastases from solid tumors or multiple myeloma, in conjunction with antineoplastic therapy. Research has indicated that Zometa may have properties that lend to direct antineoplastic effects, an issue that is being explored in studies at present. Researchers also continue to evaluate Zometa in early stages of various types of cancer to assess its effectiveness in the prevention of bone metastasis and other outcome endpoints, with over 20,000 patients in 10 different countries enrolled in Zometa trials at present.

Biphopshonates are approved for treatment of osteoporosis and to prevent skeltal related events (fractures) in certain cancer patients with bone or other metastases. Clodronate, or ibandronate may delay or prevent bone metastases in patients with nonmetastatic breast cancer and are being studied for adjuvant therapy. In addition to the ABCSG-012 trial, which is reported below, the parallel-design Zometa®/Femara® Adjuvant Synergy Trials (Z-FAST and ZO-FAST in the U.S. and Europe, respectively) are investigating the benefit of immediate and delayed treatment with zoledronic acid (4 mg every 6 months) in postmenopausal women receiving adjuvant therapy with letrozole (2.5 mg/day) for early-stage hormone-receptor-positive breast cancer. Those trials will also enroll women in whom menopause has been induced by chemotherapy. The poposed trial is ongoing. Based on the results from early clinical trials, bisphosphonates appear to be effective for the prevention of fractures. Current consensus guidelines from the American Society of Clinical Oncology recommend the use of i.v. or oral bisphosphonate therapy in patients who develop T scores below -2.5 standard deviations from normal (osteoporosis) during adjuvant therapy for breast cancer.

NCT00127205, is a study of Zoledronate, Clodronate, or Ibandronate in Treating Women Who Have Undergone Surgery for Stage I, Stage II, or Stage III Breast Cancer. It is not yet known whether zoledronate is more effective than clodronate or ibandronate in treating breast cancer.

However,the Austrian Breast & Colorectal Cancer Study Group Trial 12 (ABCSG-21)reported that the addition of adjuvant Zometa® (zoledronic acid) to endocrine therapy for the treatment of hormone-positive, early breast cancer significantly improved progression-free and recurrence-free survival beyond the effects of endocrine therapy alone among premenopausal women. These results were recently presented as a late-breaking abstract at the 2008 annual American Society for Clinical Oncology (ASCO) meeting in Chicago, Illinois May 30 to June 2, 2008.

This was a multicenter, open-label Phase III study that included 1,803 premenopausal women with Stages I-II, hormone-positive breast cancer. Compared with hormone therapy alone, the addition of Zometa improved disease-free survival by 36% (p=0.01) and recurrence-free survival by 35% (p=0.015).

Researchers affiliated with the Austrian Breast & Colorectal Cancer Study Group Trial 12 (ABCSG-21) have reported that the addition of adjuvant Zometa® (zoledronic acid) to endocrine therapy for the treatment of hormone-positive, early breast cancer significantly improved progression-free and recurrence-free survival beyond the effects of endocrine therapy alone among premenopausal women. These results were recently presented as a late-breaking abstract at the 2008 annual American Society for Clinical Oncology (ASCO) meeting in Chicago, Illinois May 30 to June 2.

The current study, the Austrian Breast & Colorectal Cancer Study Group Trial 12 (ABCSG-21), was a multicenter, open-label Phase III study that included 1,803 premenopausal women with Stages I-II, hormone-positive breast cancer. Patients had fewer than 10 involved axillary lymph nodes. Following curative surgery and initiation of the gonadotropin-releasing hormone analog goserelin for ovarian suppression, patients were enrolled and randomized into one of four treatment groups: 1) Arimidex® (anastrozole) plus Zometa; 2) Arimidex alone; 3) Nolvadex® (tamoxifen) plus Zometa; 4) Nolvadex alone. Treatment was continued for three years; the median follow-up of the trial was five years. Disease-free survival in all treatment groups was the primary endpoint; recurrence-free survival, overall survival and safety were secondary endpoints. Bone-metastases-free survival was an exploratory endpoint of the trial.

Compared with hormone therapy alone, the addition of Zometa improved disease-free survival by 36% (p=0.01) and recurrence-free survival by 35% (p=0.015).

Patients treated with Zometa had a survival of 98% compared with 94% for the control group (p=0.10).
Patients treated with Zometa had a trend toward a lower risk of developing bone metastases (p>0.05).
Longer follow-up and a larger number of events are necessary to truly determine significance of overall survival and the risk of the development of bone metastases.

There were no reported cases of osteonecrosis of the jaw (ONJ); side effects were consistent with the known drug safety profile. These are among the first data to suggest that there is a specific anti-tumor effect of bisphosphonates in anadjuvant setting.

It is recommended that, if available, zoledronic acid (4 mg intravenously [over 15 minutes or longer] every 6 months [for 3 to 5 years]) or clodronate (1,600 mg/d orally [for 2 to 3 years]) be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy.
Sukhbinder Dhesy-Thind et al, Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology 35, no. 18 (June 2017) 2062-2081.

Reid IR, Brown JP, Burckhardt P et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653–661

Gnant M, Hausmaninger H, Samonigg H et al. Changes in bone mineral density caused by anastrozole or tamoxifen in combination with goserelin (± zoledronate) as adjuvant treatment for hormone receptor-positive premenopausal breast cancer: results of a randomized multicenter trial. Presented at the 25th Annual San Antonio Breast Cancer Symposium, December 11–14, 2002, San Antonio, TX.

Saarto T, Blomqvist C, Valimaki M et al. Clodronate improves bone mineral density in post-menopausal breast cancer patients treated with adjuvant antioestrogens. Br J Cancer 1997;75:602–605

Allan Lipton Toward New Horizons: The Future of Bisphosphonate Therapy The Oncologist, Vol. 9, Suppl 4, 38–47, September 2004