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Sheffield, United Kingdom

Rathbone E.J.,Academic Unit of Clinical Oncology
Journal of clinical oncology : official journal of the American Society of Clinical Oncology

In patients with early breast cancer, adjuvant zoledronic acid (zoledronate) may reduce recurrence and improve survival. However, zoledronate is associated with the occasional development of osteonecrosis of the jaw (ONJ). We report on the frequency of ONJ and investigate oral health-related quality of life (Oral-QoL) in a large randomized trial (Adjuvant Zoledronic Acid to Reduce Recurrence [AZURE]). Three thousand three hundred sixty women with stage II or III breast cancer were randomly assigned to receive standard adjuvant systemic therapy alone or with zoledronate administered at a dose of 4 mg for 19 doses over 5 years. All potential occurrences of ONJ were reported as serious adverse events and centrally reviewed. Additionally, we invited 486 study participants to complete the Oral Health Impact Profile-14 (OHIP-14) to assess Oral-QoL around the time the patients completed 5 years on study. Multivariable linear regression was used to calculate mean scores and 95% CIs in addition to identifying independent prognostic factors. With a median follow-up time of 73.9 months (interquartile range, 60.7 to 84.2 months), 33 possible cases of ONJ were reported, all in the zoledronate-treated patients. Twenty-six cases were confirmed as being consistent with a diagnosis of ONJ, representing a cumulative incidence of 2.1% (95% CI, 0.9% to 3.3%) in the zoledronate arm. Three hundred sixty-two patients (74%) returned the OHIP-14 questionnaire. Neither the prevalence nor severity of impacts on Oral-QoL differed significantly between zoledronate patients and control patients. Adjuvant zoledronate used in the intensive schedule studied in the AZURE trial is associated with a low incidence of ONJ but does not seem to adversely affect Oral-QoL. Source

Winter M.C.,Weston Park Hospital | Coleman R.E.,Academic Unit of Clinical Oncology
Clinical Oncology

Bisphosphonates, as potent inhibitors of osteoclast-mediated bone resorption, significantly reduce the risk of skeletal complications in metastatic bone disease and also prevent cancer treatment-induced bone loss (CTIBL). However, more recently, there has been increasing data indicating that bisphosphonates exhibit anti-tumour activity, possibly via both indirect and direct effects, and can potentially modify the metastatic disease process providing more than just supportive care. The evidence from previous studies of an anti-tumour effect of bisphosphonates was inconclusive, with conflicting evidence from adjuvant oral clodronate trials. However, more recent trials using zoledronic acid have shown benefits in terms of disease-free and overall survival outcomes in certain subgroups, most evidently in older premenopausal women with hormone-sensitive disease treated with ovarian suppression, and in women in established menopause at trial entry. In the adjuvant setting, the use of bisphosphonates has also been focused on the prevention and treatment of CTIBL and recent guidelines have defined treatment strategies for CTIBL. The role of bisphosphonates in CTIBL in early breast cancer is well defined. There have been mixed results from large adjuvant metastasis-prevention studies of bisphosphonates, but there are strong signals from large subgroups analyses of randomised phase III trials suggesting significant anti-tumour beneficial effects in specific patient populations. © 2012 The Royal College of Radiologists. Source

Hadji P.,University of Marburg | Coleman R.,Academic Unit of Clinical Oncology | Gnant M.,Medical University of Vienna | Green J.R.,Novartis
Annals of Oncology

Recent data from the AZURE, ABCSG-12, and ZO-FAST clinical trials have challenged our understanding of the potential anticancer activity of zoledronic acid (ZOL). Although the results of these studies may appear to be conflicting on the surface, a deeper look into commonalities among the patient populations suggest that some host factors (i.e. patient age and endocrine status) may contribute to the anticancer activity of ZOL. Indeed, data from these large clinical trials suggest that the potential anticancer activity of ZOL may be most robust in a low-estrogen environment. However, this may be only part of the story and many questions remain to be answered to fully explain the phenomenon. Does estrogen override the anticancer activity of ZOL seen in postmenopausal women? Are hormones other than estrogen involved that contribute to this effect? Does the role of bone turnover in breast cancer (BC) growth and progression differ in the presence of various estrogen levels? Here, we present a review of the multitude of factors affected by different endocrine environments in women with BC that may influence the potential anticancer activity of ZOL. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. Source

Coleman R.E.,Academic Unit of Clinical Oncology
Current Opinion in Supportive and Palliative Care

Purpose of review Bone-targeted treatments with bisphosphonates (e.g., zoledronic acid) and denosumab are known to reduce the risk of skeletal complications and prevent treatment-induced bone loss in patients with malignant bone disease. Additionally, these drugs may modify the course of bone destruction via inhibitory effects on the 'vicious cycle' of growth factor and cytokine signalling between tumour and bone cells within the bone marrow microenvironment. Recent findings In early stage breast cancer, treatment with zoledronic acid has shown improvements in disease-free and overall survival, notably in women with established menopause at diagnosis and in premenopausal women with endocrine-responsive disease, treated with goserelin to suppress ovarian function. Other bisphosphonates such as clodronate may produce similar benefits. Additionally, in castrate-resistant prostate cancer, treatment with denosumab delays the development of bone metastases. Summary These results strongly support the adjuvant use of bone-targeted treatments, but suggest that reproductive hormones are an important treatment modifier to take into account. © 2012 Wolters Kluwer Health | Lippincott Williams &Wilkins. Source

Coleman R.,Academic Unit of Clinical Oncology | MacCallum P.,Queen Mary, University of London
British Journal of Cancer

Patients with cancer who develop venous thromboembolism (VTE) are at elevated risk for recurrent thrombotic events, even during anticoagulant therapy. The clinical picture is further complicated because these patients are also at increased risk of bleeding while on anticoagulants. In general, there are four key goals of treatment for VTE: preventing fatal pulmonary embolism (PE); reducing short-term morbidities associated with acute leg or lung thrombus; preventing recurrent VTE; and preventing the long-term sequelae of VTE (e.g., post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension). A fifth goal - minimising the risk for bleeding while on anticoagulation - is particularly warranted in patients with cancer. Traditionally, pharmacological treatment of VTE has two phases, with the transition between phases marked by a switch from a rapid-acting, parenterally administered anticoagulant (such as unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux) to an oral vitamin K antagonist (e.g., warfarin). Recent clinical trials of established agents and the advent of new pharmacological options are changing this paradigm. Low-molecular-weight heparin continued for 6 months is more effective than warfarin in the secondary prevention of VTE in cancer patients without increasing the risk of bleeding and is now the preferred treatment option. Given the impact of VTE on short-term and long-term outcomes in patients with cancer, a group of health-care providers based in the United Kingdom gathered in London in 2009 to discuss recent data on cancer-associated thrombosis and to evaluate how these recommendations can be integrated or translated into UK clinical practice. This article, which is the third of four articles covering key topics in cancer thrombosis, focuses on treatment and secondary prevention of VTE in cancer patients. © 2010 Cancer Research UK. All rights reserved. Source

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