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• W2052604036 abstract "The recently published article by Scagliotti et al.1Scagliotti GV Hirsh V Siena S et al.Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.JThorac Oncol. 2012; 7: 1823-1829Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar reports the results of an explorative study performed on a subset of patients with bone metastatic lung cancer, enrolled in a large, prospective, phase III trial, which compared the efficacy of denosumab plus standard antineoplatic therapy versus zoledronic acid plus standard therapy. The results showed that denosumab-treated patients obtained a significant survival improvement over zoledronic acid-treated ones. The greater potency of denosumab than zoledronic acid in decreasing bone turnover is conceivably the major mechanism responsible for the results obtained, so these data further underline the importance of targeting bone microenvironment in the management of patients with metastatic cancer. In the two randomized clinical trials with the same design, conducted in patients with breast and prostate cancer,2Stopeck AT Lipton A Body JJ et al.Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.J Clin Oncol. 2010; 28: 5132-5139Crossref PubMed Scopus (1236) Google Scholar,3Fizazi K Carducci M Smith M et al.Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study.Lancet. 2011; 377: 813-822Abstract Full Text Full Text PDF PubMed Scopus (1558) Google Scholar however, denosumab failed to demonstrate a survival advantage over zoledronic acid. How can we explain this discrepancy? All these trials showed that the greater bone turnover inhibition induced by denosumab led to a greater incidence of hypocalcemia than zoledronic acid. However, hypocalcemia was more frequent in patients with bone lesions with a greater blastic component, that is, 13% in prostate cancer versus 8.6% in lung cancer patients after denosumab (the frequency of hypocalcemia in the breast cancer trial was not reported). The consequence of hypocalcemia is secondary hyperparathyroidism and this condition can adversely affect the efficacy of bone resorption inhibitors by several mechanisms: (1) parathyroid hormone (PTH) increases the availability of cytokines and growth factors in bone microenvironment, (2) PTH has an amino-terminal sequence homology with PTH-related protein, a potent growth factor, and PTH-related protein and PTH bind to the same receptor that is expressed in cancer cells. In an explorative analysis performed on the data of a multinational trial of bone metastatic prostate cancer patients who were randomized to receive zoledronic acid or placebo,4Berruti A Cook R Saad F et al.Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients undergoing zoledronic acid administration.Oncologist. 2012; 17: 645-652Crossref PubMed Scopus (18) Google Scholar secondary hyperparathyroidism was a negative predictor of zoledronic acid efficacy in terms of survival. On these grounds, an interesting hypothesis is that secondary hyperparathyroidism may limit the efficacy of denosumab. If this hypothesis is true, then a vitamin D supplementation tailored to counteract individual hypocalcemia can improve the drug efficacy in terms of survival. In the explorative study by Scagliotti et al.,1Scagliotti GV Hirsh V Siena S et al.Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.JThorac Oncol. 2012; 7: 1823-1829Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar therefore, it would be interesting to know whether the efficacy of denosumab versus zoledronic acid is improved in the patient subset that did not experience hypocalcemia after denosumab, as opposed to those patients developing this metabolic disturbance." @default.
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• W2052604036 date "2013-08-01" @default.
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• W2052604036 title "Why Denosumab Obtains a Survival Benefit over Zoledronic Acid in Bone Metastatic Lung Cancer Patients?" @default.
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