Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases: the state of the art.

Most women with advanced breast cancer will develop bone metastases, which are associated with the development of skeletal-related events (sres) such as pathologic fractures and spinal cord compression. This article reviews the evolving definition and incidence of sres, the pathophysiology of bone metastases, and the key evidence for the safety and efficacy of the currently available systemic treatment options for preventing and delaying sres in the setting of breast cancer with bone metastases.The bisphosphonates are structural analogues of endogenous pyrophosphate; three of them (clodronate, pamidronate, and zoledronate) are currently approved for use in Canada in the setting of breast cancer with bone metastases. Denosumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human rankl (receptor activator of nuclear factor κB ligand), thereby preventing osteoclast formation, function, and survival, and reducing cancer-induced destruction of bone. Denosumab has recently been approved in Canada for reducing the risk of sres from the bone metastases associated with a variety of malignancies, including breast cancer. How to predict the patients that will benefit most from prophylactic treatment, the agents to select and the timing of switches between agents, the dosing schedules and durations of treatment to choose, the potential utility of the agents in the adjuvant setting, and the utility of additional endpoints such as markers of bone resorption are among the outstanding questions with respect to the optimal use of antiresorptive agents for patients with breast cancer and bone metastases.

A teaching model for aromatase inhibitors after tamoxifen.

Breast cancer is the most common cancer diagnosed in women. The present study evaluated the family physicians' (FPs) understanding of adjuvant hormonal therapies for an early breast cancer. FPs were invited to attend teaching workshops on this topic, which utilized a pretest, didactic and interactive teaching, and posttest format. FPs (n = 23) showed an improvement (p < 0.001) in pretest to posttest score. It is clear that, with a targeted teaching, FPs can quickly become more knowledgeable on the topic of hormonal therapies in breast cancer, with the potential of applying this information in their own practice.

Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel.

Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3-4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.

High-dose mitoxantrone-vinblastine-cyclophosphamide and autologous stem cell transplantation for stage III breast cancer: final results of a prospective multicentre study.

BACKGROUND: Stage III breast cancer patients continue to suffer high relapse and death rates despite standard chemotherapy regimens. High-dose alkylator chemotherapy does not further improve outcome. This phase II study evaluated a novel high-dose chemotherapy regimen which combined active breast cancer agents with differing mechanisms of action. PATIENTS AND METHODS: Eligibility included at least seven involved axillary nodes (AxLNs) for tumours <5 cm, at least four AxLNs for tumours >5 cm or locally advanced breast cancer (LABC). Patients received four cycles of fluorouracil-adriamycin-cyclophosphamide (FAC) followed by one cycle of mitoxantrone 63 mg/m(2)-vinblastine 12.5 mg/m(2)-cyclophosphamide 6 g/m(2) (MVC) with autologous blood stem cell transplantation (ASCT). RESULTS: Between April 1995 and December 1998, 92 patients aged 21-65 years (median 45 years) were enrolled, of whom 25 were treated preoperatively for LABC and 67 were treated postoperatively. Although there was no early treatment-related mortality, one late death occurred from secondary acute myeloid leukaemia. The 7-year event-free and overall survival rates were 53% (95% confidence interval 42-64%) and 62% (95% CI 52-73%), respectively, with no significant difference between pre- and postoperative groups. CONCLUSION: FAC followed by MVC-ASCT is feasible and reasonably well tolerated, but does not result in improved survival rates compared with other conventional or high-dose regimens for stage III breast cancer.

Bisphosphonates: biological response modifiers in breast cancer.

Bone recurrence constitutes one third of initial sites of relapse and one half of distant sites of relapse at 10 years from diagnosis of breast cancer. Bone pain, fracture (including vertebral fracture resulting from increased bone resorption following chemotherapy-induced menopause), and hypercalcemia are components of skeletal morbidity. The pathophysiology of malignant osteopathy occurs because of the secretion of substances (such as parathyroid hormone-related peptide), by the malignant cell, which stimulate osteoclast function; this in turn feeds further growth, which causes a vicious cycle. Interruption of this cycle by bisphosphonates may inhibit the growth of malignant cells. Bisphosphonates are drugs that inhibit bone turnover by decreasing bone resorption. Side effects of bisphosphonates include upper gastrointestinal symptoms (in oral nitrogen-containing bisphosphonates) and diarrhea (in oral non-nitrogen-containing bisphosphonates) and an acute phase-like reaction with intravenous (I.V.) pamidronate. Bisphosphonates have different molecular mechanisms of action: Nitrogen-containing bisphosphonates (eg, pamidronate and alendronate) inhibit the mevalonate-signaling pathway while the non-nitrogen-containing drugs (eg, clodronate) incorporate into adenosine triphosphate analogues. There is in vitro evidence that these drugs also possess anticancer properties. In hypercalcemia patients, treatment with pamidronate and zoledronate produce prompt and efficient normocalcemia. Intravenous pamidronate and zoledronate, oral clodronate, and ibandronate reduce skeletal complications in patients with bone metastases; I.V. pamidronate and clodronate are useful for bone pain relief. Three adjuvant bisphosphonate trials are discussed herein: 2 small open-label studies giving conflicting results and a large placebo-controlled trial of oral clodronate. This latter trial shows a reduction in the incidence of skeletal metastases (while the patients are on therapy) and an improved survival at 5 years.