{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T11:19:12Z","timestamp":1773832752102,"version":"3.50.1"},"reference-count":37,"publisher":"Wiley","issue":"S10","license":[{"start":{"date-parts":[[2009,4,28]],"date-time":"2009-04-28T00:00:00Z","timestamp":1240876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Genentech, Novartis Pharmaceuticals, Pfizer, Inc., and Wyeth Pharmaceuticals"},{"name":"Bayer\/Onyx, Genetech, and Wyeth"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2009,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Several novel therapies have been approved recently in advanced renal cell carcinoma (RCC). These agents inhibit pathways downstream of loss of the von Hippel\u2010Lindau gene <jats:italic>VHL<\/jats:italic>. They target the vascular endothelial growth factor (<jats:italic>VEGF<\/jats:italic>) ligand, VEGF receptor (VEGFR), mammalian target of rapamycin (mTOR), and other potentially important pathways. Even with improvements in survival, disease progresses in all patients. There is a critical need to increase complete responses (now rare). One such strategy is combining several agents to block different levels of the VEGF\u2010VEGFR axis (vertical blockade). Alternatively, combination of a VEGF\u2010VEGFR inhibitor with an mTOR inhibitor is attractive. Finally, horizontal blockade of VEGFR with epidermal growth factor receptor and\/or platelet\u2010derived growth factor receptor, all signaling pathways activated by hypoxia\u2010inducible factor, is another approach. Already trials have revealed difficulties with combination therapy. By combining agents, the toxicity of 1 or both can be enhanced. The authors of this article report their experience with sorafenib plus bevacizumab, which produced increases in hand\u2010foot syndrome, hypertension, and proteinuria, all known toxic effects. Clinical activity was impressive with 25 responses in 48 patients (52% response rate). Other combinations also required dose reductions (sorafenib with temsirolimus) or were intolerable (sunitinib with temsirolimus or sunitinib with bevacizumab). Unexpected toxicity characterized by microangiopathic hemolytic anemia occurred late in treatment with sunitinib and bevacizumab. Toxicity may be more severe in patients with RCC, who frequently have 1 kidney and poor renal function. Once tolerability for combination regimens has been established, it will be critical to design informative phase 2 trials and address the benefit of combination versus sequential therapy. Cancer 2009;115(10 suppl):2368\u201075. \u00a9 2009 American Cancer Society.<\/jats:p>","DOI":"10.1002\/cncr.24234","type":"journal-article","created":{"date-parts":[[2010,3,2]],"date-time":"2010-03-02T12:47:40Z","timestamp":1267534060000},"page":"2368-2375","source":"Crossref","is-referenced-by-count":37,"title":["Combination targeted therapy in advanced renal cell carcinoma"],"prefix":"10.1002","volume":"115","author":[{"given":"Jeffrey","family":"Sosman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Puzanov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,4,28]]},"reference":[{"issue":"1","key":"e_1_2_8_2_2","first-page":"S55","article-title":"Long\u2010term survival update for high\u2010dose recombinant interleukin\u20102 in patients with renal cell carcinoma","volume":"6","author":"Fisher 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