Expanded Role for Bisphosphonates in Metastatic Breast Cancer

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

Furthermore, he said, data now suggest that bisphosphonates may be ableto prevent the development of bone metas-tases in patients with advancedbreast cancer and possibly prevent bone loss in patients who have earlymenopause as a result of chemotherapy.

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

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

In a new study, published this year, Dr. Paterson's group showed thatthe agent appears to prevent the growth of bone metastases. Women withrecurrent breast cancer but no evidence of bone metastases at trial entrywere 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-relatedevents in the clodronate group and a trend toward a reduction in the diagnosisof new bone metastases in the clodronate group.

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

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

Bone mineral density was measured before entry and at one, two, andthree years. At two-year follow-up of over 300 patients, the clodronatepatients 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 rateof loss was reduced in the clodronate patients. In the tamoxifen (Nolvadex)-treatedpostmenopausal patients, tamoxifen provided some protection against boneloss, but the placebo patients still showed a slight loss of bone at oneyear whereas the clodronate patients had a gain in bone density.

Pamidronate Study

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

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

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

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

There were significant numerical differences in the number of skeletal-relatedevents, with fewer events in the pamidronate-treated group in both protocols,Dr. Hortobagyi reported. Pam-idronate was also clearly favored in termsof 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. Therehave been no differences in survival to date.