Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma.
The plethora of novel agents recently approved for the management of metastatic renal cell carcinoma (RCC) has changed the therapeutic landscape in this disease. The plethora of targets some of these agents inhibit can result in a wide range of side effects. While these novel therapies can be viewed as inhibitors of angiogenesis that directly or indirectly target the vascular endothelial growth factor (VEGF) pathway, their individual mechanisms of action (MoA) are key to defining their side-effect profiles. Direct VEGF inhibition with the anti-VEGF monoclonal antibody bevacizumab, is primarily associated with side effects related to the precise inhibition of VEGF, such as proteinuria, hypertension and minor bleeding events. In contrast, non-VEGF-related side effects are observed with agents inhibiting multiple receptor tyrosine kinases (sunitinib, sorafenib, axitinib and pazopanib) and mammalian target of rapamycin inhibitors (temsirolimus and everolimus); these include diarrhoea, skin rash, stomatitis, hand-foot skin reaction, hypothyroidism, and haematological and metabolic abnormalities. This review discusses the MoA of these novel therapies and how a greater understanding of MoA may help to predict the range and type of side effects, develop combinations of agents with acceptable tolerability, enable a more rational approach to patient selection, and allow the development of effective side-effect management strategies.
Schmidinger
Manuela
M
Department of Medicine I, Clinical Division of Oncology and Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. manuela.schmidinger@meduniwien.ac.at
Bellmunt
Joaquim
J
D020533:Angiogenesis Inhibitors / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab