New Frontiers in Treatment
In the United States, prostate cancer is the most common cancer in men, with an estimated 220,000 cases diagnosed in 2015 [1]. With a percentage of involvement of more than 80 %, the bone represents the preferential site of metastases for this disease. As
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Sergio Bracarda, Alketa Hamzaj, and Kalliopi Andrikou
In the United States, prostate cancer is the most common cancer in men, with an estimated 220,000 cases diagnosed in 2015 [1]. With a percentage of involvement of more than 80 %, the bone represents the preferential site of metastases for this disease. As a consequence, patients experiencing advanced stage castrationresistant prostate cancer (CRPC) are at increased risk of developing skeletal-related events, including pathologic fractures and spinal cord compression [2]. Despite recent important therapeutic advances in the management of CRPC, there is a continuous medical need to develop further treatment options to overcome the mechanisms of resistance of surviving prostate cancer cells, such as the splice variants of the androgen receptor (AR). All the possible new agents, or combinations, with efficacy data in the area of prostate cancer have been analyzed. Data are presented according to the mechanism of action of the single agents.
S. Bracarda, MD (*) • A. Hamzaj, MD K. Andrikou, MD Medical Oncology, Department of Oncology Azienda USL Toscana Sud-Est, Istituto Toscano Tumori (ITT), Ospedale San Donato, Arezzo, Italy e-mail: [email protected]
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Vascular Endothelial Growth Factor (VEGF) Targeting Therapies
In prostate cancer, the VEGF signaling pathway seems to be para-physiological for disease progression: higher levels of VEGF receptor (VEGFR)-2 are observed in high-grade prostate cancer, while patients with metastatic prostate cancer have higher serum VEGF levels and levels of urine and serum VEGF seem to relate with overall survival (OS), in subjects with metastatic CRPC (mCRPC). VEGFRs are also expressed in human osteoblasts and osteoclasts with the VEGF pathway involved in mechanisms regulating cell migration and survival [3–5]. Moreover, VEGF treatment inhibits the apoptosis of human osteoblasts by increased expression of the Bcl-2, an antiapoptotic protein, as demonstrated in vitro [5]. All these findings suggest an important role for the VEGF signaling pathway in the processes of prostate cancer progression and bone metastasis. Several agents targeting angiogenesis have been evaluated in phase III clinical trials in CRPC, but no one demonstrated a clinical benefit in men with CRPC.
17.1.1 Bevacizumab Bevacizumab is a recombinant, humanized monoclonal antibody blocking VEGF activity. In
© Springer International Publishing Switzerland 2017 F. Bertoldo et al. (eds.), Bone Metastases from Prostate Cancer, DOI 10.1007/978-3-319-42327-2_17
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CALGB 90006, a phase II study, 79 patients with chemotherapy-naïve metastatic CRPC received bevacizumab 15 mg/kg combined with docetaxel and estramustine. The progression-free survival (PFS) and median OS were 8 and 24 months, respectively. The observed improvement in OS led to plan a phase III study despite this study did not meet its primary endpoint of PFS [6]. The phase III, double-blind, placebo-controlled study, CALGB 90401, randomized 1050 chemothera
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