[MOL] Part 9 of series of 11 [01095]

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American Society of Clinical Oncology 35th Annual Meeting
Day 1 - May 15, 1999

Bisphosphonate Therapy in Metastatic Breast Cancer

Joseph Sparano, MD -- Writer: Michelle L. Plante, PharmD

Skeletal metastases occur in up to 70% of patients with metastatic breast cancer, frequently producing substantial morbidity, including bone pain, pathologic fracture, spinal cord compression, and hypercalcemia. These clinical manifestations are a result of local protease-mediated tissue destruction and an imbalance in the normal homeostasis favoring osteolysis (mediated by osteoclasts) over bone formation (mediated by osteoblasts). The bisophosphonates are a group of agents that interfere with tumor-mediated osteolysis by modulating the function, maturation, and recruitment of osteoclasts. Pamidronate and clodronate are the most extensively studied bisphosphonates in breast-cancer patients.

It is now well established that pamidronate, at a dose of 90 mg given intravenously (IV) every 3-4 weeks, reduces the incidence of skeletal complications by about 30%, without altering survival, in women with metastatic breast cancer and osteolytic bone metastases who are receiving chemotherapy or hormonal therapy. In fact, it is currently approved in the United States for the palliation of osteolytic skeletal metastases due to breast cancer or multiple myeloma. The benefits associated with this treatment must be weighed against the cost and inconvenience of requiring a 2-hour intravenous infusion of the drug every 3-4 weeks for up to 2 years or longer.

Two previous studies have also evaluated the role of an orally administered bisphosphonate (clodronate) in early-stage breast cancer. Diel and colleagues^[1] have shown that oral clodronate (1600 mg/day) given for 2 years reduced the incidence of skeletal and nonskeletal metastases and improved survival in women with stage I/II breast cancer who had micrometastases demonstrated on bone marrow examination. Powles^[2] reported at last year's ASCO meeting that although adjuvant clodronate reduced the incidence of skeletal metastases, it had no influence on the incidence of nonskeletal metastases, disease-free survival, or overall survival in women with early-stage breast cancer. Two reports on the first day of this year's ASCO conference provided some new information on this topic.

Pamidronate vs Clodronate

Diel^[3] from the University of Heidelberg in Germany presented the preliminary results of a randomized trial comparing these 2 agents. This was a 3-arm trial involving 318 women with metastatic breast cancer and osteolytic bone metastasis. Patients were randomized to receive pamidronate 60 mg IV every 3 weeks, clodronate 900 mg IV every 3 weeks, or oral clodronate 2400 mg/day. Patients concurrently received "standard therapy" for their metastatic breast cancer. The median follow-up at the time of the analysis was 18 months.

More patients in the IV clodronate arm had vertebral fractures (n=20 fractures) compared with the oral clodronate arm (n=12) or the IV pamidronate (n=13) arm. About one half of the fractures were asymptomatic and detected on routine x-rays performed at 6-month intervals. More patients experienced significant pain reduction in the IV pamidronate (30%) and clodronate (25%) groups, compared with oral clodronate (15%). There was no difference in the time to progression of pain, the fracture-free survival, the radiation-free interval, or performance status among the 3 arms.

Overall, the toxicity of these regimens was low. The most common toxicity was gastrointestinal complaints, which occurred in 9% of the patients treated with oral clodronate. Infusion-related reactions occurred in 2% of patients receiving the IV preparations. This study suggests that oral clodronate may be a suitable alternative to IV pamidronate. However, it is unclear whether the 60-mg dose of pamidronate used in this study is as efficacious as the approved dose of 90 mg. Furthermore, the event rate in each arm was relatively low and the follow-up was relatively short. When the data become sufficiently mature, meaningful interpretation may be limited by the less than standard dose of pamidronate in the control arm.

The second report examined the role of bisphosphonate therapy in the adjuvant treatment of early-stage breast cancer. Saarto,^[4] from Helsinki University Central Hospital, presented the results of a Phase III trial comparing oral clodronate (1600 mg/day for 3 years) versus no bisphosphonate therapy in 295 women with axillary node-positive early-stage breast cancer. Premenopausal women received adjuvant chemotherapy (CMF ´ 6 cycles), and postmenopausal women received hormonal therapy (tamoxifen 20 mg or toremifene 60 mg daily ´ 3 years). Clodronate was given concomitantly with the systemic therapy. Follow-up in this trial was at least 5 years.

In contrast to the previous reports, clodronate use was not associated with a decrease in skeletal metastases. It was, however, associated with a significant increase in the development of nonskeletal metastases (45% vs 27%). Furthermore, clodronate use was associated with a significantly worse 5-year disease-free survival (52% vs 69%) and overall survival (68% vs 81%). This deleterious effect was most pronounced in patients with estrogen-receptor-negative disease (5-year disease-free survival of 35% vs 64%), and was not present in the ER-positive group (66% vs 72%). When the analysis was adjusted in a multivariate model that incorporated recognized prognostic variables, clodronate was still associated with a significantly worse disease-free survival but not overall survival. This was attributed to the significant increase in the incidence of nonskeletal metastases associated with clodronate.

Putting It in Perspective

Although Diel's report suggests that oral clodronate is equally efficacious to IV pamidronate in patients with metastatic breast cancer, comparison with standard dose of pamidronate is lacking. Therefore, until randomized studies of this nature are conducted, 90 mg of pamidronate administered IV every 3-4 weeks should remain the standard of care for patients with osteolytic bone metastases.

It is not clear why Saarto's data contrast so sharply with previous reports. With regard to adjuvant therapy, the data at this point are currently insufficient to recommend routine use of bisphosphonates as a component of adjuvant therapy for patients with early-stage disease. This also is an area that future randomized clinical trials should address.

References

Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357-363.
Powles TJ, Paterson AHG, Nevantaus A, et al. Adjuvant clodronate reduces the incidence of bone metastases in patients with primary operable breast cancer [Abstract 468]. American Society of Clinical Oncology 34th Annual Meeting, Los Angeles, 1998.
Diel IJ, Marschner N, Kindler M, et al. Continual oral versus intravenous interval therapy with bisphosphonates in patients with breast cancer and bone metastases [Abstract 488]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.
Saarto T, Blomqvist C, Pekka V, et al. No reduction of bone metastasis with adjuvant clodronate treatment in node-positive breast cancer patients [Abstract 489]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999.

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