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Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomized trials

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)*

The Lancet, In Press, Corrected Proof, Available online 23 July 2015

Selected and commented by Dr. Anton Snegovoy

Most cancers metastasize to the bone, for example cancer of the breast, prostate, thyroid gland, kidney, bladder and lung. The clinical picture of metastatic bone disease is characterized by pain, hypercalcemia, fractures and neurological symptoms. The appearance of skeletal complications is accompanied by increased mortality and decreased quality of life. According to an observational study by Lipton et al., involving 751 patients with breast cancer and bone metastases, more than 60% had marked skeletal complications, accounting for 3.7 cases per year [1].

This makes prophylactic bisphosphonate treatment look tempting. Moreover, experimental research indicated a direct antitumor effect of bisphosphonates, confirming the need for more research in this field. In 1998, Prof. Diel published the first paper which showed the effectiveness of adjuvant clodronate in postmenopausal women with breast cancer [2]. However, subsequent studies were contradictory.

References

[1] 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: long term follow-up of two randomized placebo-controlled trials. Cancer 2000; 88(5): 1082–90

[2] Diel IJ, Solomayer E, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Eng J Med 1998; 339(6): 357–63

Summary


Background
Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer.

Methods
We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs).

Findings
We received data on 18 766 women (18 206 [97%] in trials of 2–5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87–1·01; 2p=0·08), distant recurrence (0·92, 0·85–0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83–0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73–0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002), distant recurrence (0·82, 0·74–0·92; 2p=0·0003), bone recurrence (0·72, 0·60–0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73–0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75–0·97; 2p=0·02).

Interpretation
Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.

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