Oral bisphosphonates as adjuvant therapy for operable breast cancer

teaser

Reuben Broom
BHB MBChB FRACP

Christine Simmons
MD FRCP(C)

Mark Clemons
MB MRCP MD
Head
Breast Medical Oncology
Department of Medical Oncology
Princess Margaret Hospital
Toronto, Ontario Canada
E: [email protected]

Bone is the most common site of metastatic spread in breast cancer patients. The use of bisphosphonates in women with bone metastases from breast cancer has been shown to reduce the incidence and delay the onset of skeletal-related events. Indeed, bisphosphonates are now standard in treating patients with established bone metastases. As with all new therapies, once efficacy in the metastatic setting is demonstrated, therapies are tested in the adjuvant setting. The role of oral adjuvant bisphosphonate therapy has been studied in three randomised studies. To date, the balance of evidence suggests that such use of bisphosphonates can reduce the development of bone metastases and possibly� confer a survival advantage. These studies are reviewed in this article, as is the direction of current adjuvant oral bisphosphonate research.

Review
Approximately 80% of patients with metastatic breast cancer (MBC) develop bone disease.(1) Bone metastases cause considerable morbidity through pain and skeletal-related events (SREs). SREs can be defined as pathological fractures, need for surgery or radiotherapy to bone, hypercalcaemia or spinal-cord compression. While MBC patients with bone-predominant disease tend to live longer than those with significant visceral disease, the occurrence of an SRE portends a poorer prognosis.(2) Bisphosphonates are compounds that bind preferentially to sites of bone turnover and inhibit osteoclast-mediated bone resorption. The bisphosphonates commonly used in oncology are, in order of increasing in-vitro potency, oral clodronate (first-generation), intravenous pamidronate (second-generation), intravenous zoledronic acid (third-generation) and oral or intravenous ibandronate (also third-generation).

Randomised trials performed on patients with MBC and bone metastases consistently show that bisphosphonate treatment significantly reduces the development and delays the onset of SREs.(3-9) Three studies have demonstrated that oral clodronate could also prevent SREs in patients with known bone metastases.(10-12) Furthermore, oral clodronate reduced the development of bone metastases and SREs when given to patients with MBC but without known skeletal involvement.(13) The aforementioned research prompted the evaluation of oral clodronate in the adjuvant setting with the aim of preventing skeletal metastases and the consequent morbidity and mortality.(14,15) This article will review these adjuvant trials and comment on the current direction of adjuvant bisphosphonate research in breast cancer.

Adjuvant clodronate
Diel et al randomised 302 patients with early-stage breast cancer who had no overt bone metastases, but at least one tumour cell detected in a bone-marrow aspirate, either to receive 1,600 mg of oral clodronate daily for two years or to a control arm.(16) The presence of such cells in the marrow correlates with an increased risk of relapse. Upon occurrence of bone metastases, clodronate was continued in the treatment group and initiated in the controls. At a median follow-up of 36 months, more than twice as many patients in the control compared with the clodronate group developed distant metastases (29% vs 13 %, p < 0.001), bony metastases (17% vs 8%, p = 0.003) and visceral metastases (19% vs 8%, p = 0.003). Furthermore, almost four times as many patients died in the control arm compared with the clodronate arm (15% vs 4%, p = 0.001). The data were updated at a follow-up of 8.6 years and there was no longer a significant difference in the incidence of osseous and visceral metastases between the groups; however, a significant overall survival advantage persisted for the clodronate arm.(17)

In the largest reported adjuvant clodronate trial, Powles et al double-blindly randomised 1,069 patients with operable breast cancer to receive either oral clodronate (1,600 mg daily) or �placebo for two years.(18) If osseous relapse occurred the study medication was discontinued and bis‑phosphonate therapy was administered at the investigators’ discretion. In the final analysis (after a median �follow-up of 5.6 years), the risk of bone metastases was significantly decreased in the clodronate compared with the placebo arms (9.6 vs 13.5%, p = 0.043), equating to a risk reduction of 31%. Despite most patients receiving bisphosphonates upon osseous relapse, those patients who received adjuvant clodronate had significantly fewer SREs compared to those who received placebo. This raises the possibility of an overflow effect from the adjuvant bisphosphonate even after osseous relapse. In this study, the use of adjuvant clodronate did not significantly impact on the development of visceral metastases. There was a trend towards adjuvant clodronate conferring an overall survival advantage with the risk of death being reduced by 23% (p = 0.048). A substudy done as part of the aforementioned trial showed that clodronate, compared with placebo, could also reduce the bone loss caused by adjuvant therapy.(19)

However, the findings of the above two trials are somewhat contrary to those of Saarto et al.(20) This trial randomised 299 patients with node-positive early-stage breast cancer to either receive or not receive the same daily dose of clodronate, but for three years. Premenopausal patients also received adjuvant three-weekly intravenous CMF chemotherapy, and postmenopausal patients were further randomised to either tamoxifen or toremifene for three years. Therefore, postmenopausal hormone receptor-negative patients received endocrine therapy as opposed to chemotherapy. There were more hormone receptor-negative patients in the clodronate group.

There was no difference in the occurrence of bone metastases between groups with a similar 10-year skeletal disease-free survival (DFS). Bone was less commonly the first site of relapse in the clodronate group (11% vs 18%, p = 0.03). However, extraskeletal metastases developed more often in the clodronate group (50% vs 36%, p = 0.004). The deleterious effect of clodronate was most pronounced in the oestrogen receptor-negative patients, with 10-year DFS being 58% vs 25% (p = 0.004), respectively. Despite initial concern, with longer follow-up it has transpired that overall survival was not significantly affected by clodronate in this study.

Toxicity
Oral clodronate is generally very well tolerated. The most common side-effects of clodronate are gastrointestinal. However, in the largest of the above-mentioned trials, the only adverse effect significantly increased by its administration was diarrhoea (19.9 % vs 10.0%).(18) There were no cases of the more serious toxicities associated with some other bisphosphonates, such as oesophageal ulceration/perforation or osteonecrosis of the jaw.

Ongoing research
We are eagerly awaiting the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B34 trial. Accrual is complete for this fourth adjuvant clodronate trial, which is double-blinded and which randomised 3,323 patients to either 1,600 mg of clodronate or placebo for three years.

Several other trials are also under way, designed to evaluate the adjuvant benefit of more potent bisphosphonates. Accrual for the 3,360-patient AZURE trial is complete and this randomises patients to receive either intravenous zoledronic acid or �control in patients with lymph-node-positive disease. Ibandronate has the advantages of being less nephrotoxic than zoledronic acid(21) and is available in a smaller-sized oral preparation than clodronate. The 6,000-patient SWOG/Intergroup/NSABP S0307 trial is accruing to �evaluate its adjuvant role compared with intravenous zoledronic acid and oral clodronate. Finally, the GAIN trial, which is evaluating two chemo‑therapy regimens in node-positive breast cancer, is further randomising patients to either receive or not receive oral ibandronate.

Bisphosphonates altering treatment-induced bone loss
Aromatase inhibitors are increasingly being used in the adjuvant setting in postmenopausal women and are known to cause bone mineral loss. In addition, bone loss is often caused by chemotherapy-induced premature menopause or intentional ovarian ablation. There is a current wave of adjuvant hormone therapy trials whose arms have different bisphosphonate schedules.(22-24) While these trials provide us with insight as to how bisphosphonates can mitigate against hormone therapy-induced bone loss and consequent fractures, they may also provide us with further information about their adjuvant �benefit.

Conclusion
Thus, we have two trials suggesting a survival benefit for adjuvant clodronate, with a third small trial reporting an increase in extraosseous metastases. However, the latter open, non-placebo-controlled trial was imbalanced, with there being more hormone receptor-negative (and therefore poorer-prognosis) patients in the clodronate arm who in retrospect did not receive otherwise optimal systemic treatment. The deleterious effect of clodronate in the latter trial is therefore probably not real, and on the evidence to date, adjuvant clodronate given for two years after primary treatment is a reasonable approach, especially for high-risk patients. The results of the NSABP B34 trial will hopefully provide clarity on this issue, and further research evaluating the possibility of additional benefit from oral ibandronate is under way.

References

1. Theriault RL, Hortobagyi GN. Bone metastasis in breast cancer. Anticancer Drugs 1992;3:445-62.
2. Solomayer EF, Diel IJ, Meyberg GC, et al. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 2000;59:271-8.
3. Hortobagyi GN, Theriault RL, Lipton A, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 1998;16:2038-44.
4. Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. J Clin Oncol 1999;17:846-54.
5. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases. Cancer 2000;88:1082-90.
6. Hultborn R, Gundersen S, Ryd�n S, et al. Efficacy of pamidronate in breast cancer with bone metastases: a randomized, double-blind placebo-controlled multicenter study. Anticancer Res 1999;19:3383-92.
7. Kohno N, Aogi K, Minami H, et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 2005;23:3314-21.
8. Body JJ, Diel IJ, Lichinitzer M, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004;90:1133-7.
9. Body JJ, Diel IJ, Lichinitser MR, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399-405.
10. Paterson AHG, Powles TJ, Kanis JA, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59-65.
11. Kristensen B, Ejlertsen B, Gr�nvold M, et al. Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 1999;246:67-74.
12. Tubiana-Hulin M, Beuzeboc P, Mauriac L, et al. Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases. Bull Cancer 2001;88:701-7.
13. Kanis JA, Powles T, Paterson AH, et al. Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone 1996;19:663-7.
14. Clemons M, Rea D. Perspectives on the future of bisphosphonate use in breast cancer patients. Semin Oncol 2004;31:87-91.
15. Clemons M, Verma S. Should oral bisphosphonates be standard of care in women with early breast cancer? Breast Cancer Res Treat 2005;90:315-8.
16. Diel IJ, Solomayer EF, Costa S, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357-63.
17. J�schke A, Bastert G, Solomayer EF, et al. Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow � a longtime follow-up. Proc Am Soc Clin Oncol 2004;22:(abs 529).
18. Powles T, Paterson A, McCloskey E, et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer. Breast Cancer Res 2006;8:R13.
19. Powles TJ, McCloskey E, Paterson AHG, et al. Oral clodronate and reduction in loss of bone mineral density in women with operable primary breast cancer. J Natl Cancer Inst 1998;90:704-8.
20. Saarto T, Vehmanen L, Virkkunen P, et al. Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncologica 2004;43:650-6.
21. Bergner R, Diel IJ, Henrich D, et al. Differences in nephrotoxicity of intravenous bisphosphonates for the treatment of malignancy-related bone disease. Onkologie 2006;29:534-40.
22. Brufsky A, Harker WG, Beck JT, et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopaual women with early breast cancer. J Clin Oncol 2007;25:829-36.
23. Gnant MFX, Mlineritsch B, Luschin-Ebengreuth G, et al. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 2007;25:820-8
24. Lester JE, Gutcher SA, Ellis SP, et al. The ARIBON study: reversal of anastrozole (Arimidex�) induced bone loss with oral monthly ibandronate (Bondronat�) treatment during adjuvant therapy for breast cancer. Cancer Treat Rev 2006;32:Abstract 121.