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Expanded Role for Bisphosphonates in Metastatic Breast Cancer

Expanded Role for Bisphosphonates in Metastatic Breast Cancer

SAN ANTONIO--Bisphosphon-ates are indicated in patients with established bone metastases from breast cancer or myeloma, to reduce skeletal complications, Alexander H.G. Paterson, MD, said at a minisymposium held in conjunction with the San Antonio Breast Cancer Symposium.

Furthermore, he said, data now suggest that bisphosphonates may be able to prevent the development of bone metas-tases in patients with advanced breast cancer and possibly prevent bone loss in patients who have early menopause as a result of chemotherapy.

Dr. Paterson, professor of medical oncology, University of Calgary, Baker Cancer Centre, Alberta, described his experience with clodronate in advanced breast cancer, while Gabriel N. Hortobagyi, MD, of M.D. Anderson Cancer Center, reported on the use of pamidronate (Aredia) in these patients.

Dr. Paterson's 1992 randomized placebo-controlled study of 173 patients with metastatic breast cancer established the efficacy of clodronate in preventing skeletal complications. Those patients receiving clodronate had a significant reduction in episodes of hypercalcemia and skeletal-related events, including vertebral fractures and radiation therapy for bone pain.

In a new study, published this year, Dr. Paterson's group showed that the agent appears to prevent the growth of bone metastases. Women with recurrent breast cancer but no evidence of bone metastases at trial entry were randomized to placebo (67 patients) or oral clodronate (66 patients), 1,600 mg/day for three years.

The results clearly showed a reduction in the incidence of skeletal-related events in the clodronate group and a trend toward a reduction in the diagnosis of new bone metastases in the clodronate group.

Dr. Paterson said that the results regarding prevention of new bone lesions were not conclusive because the study was small and compliance was a problem. "Many of the patients just gave up swallowing their pills as their disease progressed," he said.

The most recent randomized trial of clodronate, started in 1991, has just completed accrual of more than 1,000 patients with operable stage I-III breast cancer receiving either chemotherapy or hormonal therapy. He reported early data on a subset of patients undergoing bone mineral density studies at the Calgary center and the Royal Marsden Hospital, London.

Bone mineral density was measured before entry and at one, two, and three years. At two-year follow-up of over 300 patients, the clodronate patients had reduced bone resorption, compared with the placebo patients.

In premenopausal patients, most of whom were receiving chemotherapy, all patients had bone loss at one- and two-year follow-up, but the rate of loss was reduced in the clodronate patients. In the tamoxifen (Nolvadex)-treated postmenopausal patients, tamoxifen provided some protection against bone loss, but the placebo patients still showed a slight loss of bone at one year whereas the clodronate patients had a gain in bone density.

Pamidronate Study

Speaking for the Aredia Breast Cancer Study Group, Dr. Hortobagyi updated the recently published multicenter study of intravenous pamidronate versus placebo in 754 patients with metastatic breast cancer and lytic bone lesions receiving chemotherapy (protocol P19) or hormonal therapy (protocol P18) as their primary cancer treatment.

Pamidronate, 90 mg administered over two hours, was given monthly to the hormonal therapy patients and every three or four weeks to the chemotherapy patients, depending on their treatment schedule. Observation periods were at 12 and 24 months.

The main endpoint was the total number of skeletal-related events, including pathologic fractures, spinal cord compression, radiation for pain relief or to treat or prevent pathologic fracture, surgery to bone, and hypercalcemia of malignancy.

Because bisphosphonates are a well-established treatment for hypercalcemia of malignancy, the data were analyzed both with and without hypercalcemic episodes, to ensure that any benefits seen with pamidronate were not restricted to hypercalcemia.

There were significant numerical differences in the number of skeletal-related events, with fewer events in the pamidronate-treated group in both protocols, Dr. Hortobagyi reported. Pam-idronate was also clearly favored in terms of the other endpoints, including proportion of skeletal-related events, morbidity rate (number of skeletal-related events divided by time in years), time to first skeletal-related event, pain relief, and analgesic use. There have been no differences in survival to date.

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