Current breast cancer clinical trials

A number of biologic effects in bone suggest that bisphosphonates have the potential to retard or prevent the clinical onset of metastatic disease. Three randomized adjuvant trials have yielded conflicting results on this question, although the use of pamidronate is now considered standard in the patients with known lytic bone metastases. A new generation of adjuvant trials is now evaluating whether bisphosphonates will reduce the rate of bone and nonbone metastases.

 

 

SELECT PUBLICATIONS

Ali SM et al. Safety and efficacy of bisphosphonates beyond 24 months in cancer patients. J Clin Oncol 2001;19(14):3434-3437. Abstract

Cristofanilli M & Hortobagyi GN. Bisphosphonates in the management of breast cancer. Cancer Control 1999;6(3):241-246. Full-Text

Diel IJ et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357-63. Abstract

Diel IJ, Mundy GR. Bisphosphonates in the adjuvant treatment of cancer: Experimental evidence and first clinical results. International Bone and Cancer Study Group (IBCG). British Journal of Cancer 2000;82:1381-6. Abstract

Hillner BE et al. For the American Society of Clinical Oncology Bisphosphonates Expert Panel. American Society of Clinical Oncology Guideline on the Role of Bisphosphonates in Breast Cancer. Full-Text

Powles TJ et al. Adjuvant clodronate reduces the incidence of bone metastases in patients with primary operable breast cancer. Proc. ASCO 1998;Abstract 468.

Saarto T et al. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 2001;19:10-17. Abstract

 

 

 

 

 

 

 

 

 

 

 

 

 

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PRIOR ADJUVANT TRIALS
There are results from three randomized trials of adjuvant clodronate. In our study, patients receiving clodronate had fewer subsequent bone and nonbone metastases. The largest study was done in Great Britain, Canada and Scandinavia. In terms of methodology, it’s the best, because it was placebo-controlled and double-blinded. They found a reduction in bone metastases but no significant effect on overall survival. The third study was done in Finland and was not placebo-controlled. In 300 node-positive patients, they observed no effect on the rate of bone metastases and a negative effect on disease-free survival and nonosseous metastases. No other bisphosphonate study has reported this type of negative effect. In addition to different methodology, the clear difference in the three studies is the selection of patients.

When we started our study ten years ago, we selected patients with tumor cells in the bone marrow, because we were convinced this was the best prognostic factor for bone metastases. Today we know it’s also a good prognostic factor for nonbone metastases, because it reflects the early hematogenous spread of breast cancer cells from the primary tumor.

Clodronate is not available in the United States, because several years ago, the initial studies reported a number of leukemias that were eventually demonstrated to be unrelated to clodronate. From that time it was not pursued as an antiosteolytic drug in the United States. The problem with the bisphosphonates is that the gastrointestinal absorption rate is low, and in order to see an effect, you need a dose that may cause side effects, particularly on the gastrointestinal tract. I support the new NSABP clodronate study, because it’s important to confirm our data, but I don’t know whether it was a good decision to include all breast cancer patients as opposed to attempting to select those most likely to develop bone metastases.

—Ingo Diel, MD

NSABP B-34: RATIONALE FOR CHOOSING CLODRONATE
Several oral and parenteral bisphosphonates are available for clinical testing in the adjuvant therapy of operable breast cancer in North America: etidronate, clodronate, alendronate, pamidronate, ibandronate, and zoledronate.
The ideal agent would be one known to be highly efficacious and conveniently administrable to ensure maximum compliance. Etidronate has been tested in myeloma and has shown no obvious efficacy in reducing skeletal complications. ... Alendronate, an oral aminobisphosphonate widely used in the treatment of osteoporosis, has not been tested in large clinical trials of patients with malignant disease. ... Pamidronate, ibandronate, and zoledronate are more potent agents but have not shown a clearly significant advantage in inhibiting malignant osteolysis. More importantly, they must be given intravenously every 3-4 weeks. ... Oral clodronate has been tested in three adjuvant trials, as well as in many metastatic bone studies, it is well tolerated; and it shows good evidence of prompt and effective inhibition of bone resorption.

— NSABP B-34 Protocol

MECHANISM OF ACTION
We have a large number of bisphosphonates either in the clinic or becoming available, and their potency is increasing. Most data are from clodronate and pamidronate — osteoclast inhibitors. Recently it was shown that these non-nitrogen-containing bisphosphonates appear to have a different mechanism of action at the cellular level than the nitrogen-containing bisphosphonates.

In advanced disease, we mostly use bisphosphonates to reduce complications in conjunction with other standard treatments. We are looking to control pain, hypercalcemia and fractures, and to reduce the requirements for radiotherapy and surgery. In adjuvant studies, clodronate reduces metastases in bone by a small amount, and in one study, there was a significant reduction in visceral metastases and an improvement in survival, but we need to do other studies to confirm this.

—Professor Anthony Howell, FRCP

 
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