TREATMENT OUTCOMES AND TOXIICIITY OF SUNIITIINIIB IIN ADVANCED RENAL CELL CARCIINOMA PATIIENTS

Abstract

Renal cell carcinoma (RCC) accounts for 2%–3% of all adult malignancies. Worldwide, there are ~209, 000 new cases and~ 102, 000 deaths per year. In the United States, RCC is currently the sixth and eighth most common malignancy among men and women, respectively, with~ 61, 560 new cases diagnosed in the US in 2015 with an estimated 14, 080 deaths.Renal cell carcinoma may remain clinically occult for most of its course, 45% of patients present with localized disease, 25% with locally advanced disease and 30% with metastatic disease. The past decade has witnessed tremendous improvements in the understanding of the role of angiogenesis in RCC, leading to the development and implementation of many angiogenesis-inhibitors, also known as targeted therapies, in clinical practice. These achievements largely stem from the elucidation of two inter-connected molecular pathways that regulate angiogenesis and proliferation in RCC, an inactivated von Hippel Lindau (VHL) gene and activated mammalian target of rapamycin (mTOR). With the expanding use of targeted agents for the treatment of metastatic renal cell carcinoma, the prognosis for this condition is shifting toward that of a chronic treatable disease. Seven targeted agents for the treatment of advanced RCC are approved from 2006 when sunitinib FDA approved till 2011: the tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib and pazopanib, the antivascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, and the mammalian target of rapamycin (mTOR) inhibitors temsirolimus and everolimus. Novel immunotherapies (eg.PD-1\PD-L1 inhipition) including nivolumab have been recently approved for evaluated in metastatic RCC. Cabozantinib, a tyrosin kinase inhipitor, is being evaluated for MET inhipition in patients who failed therapy with (VEGFR)tyrosin kinase inhipitor. Dovitinib a tyrosine-kinase inhibitor, is being evaluated for Fibroblast growth factor (FGF) receptors inhipition.FGF pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies in Patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Sunitinib, a small molecule multitarget tyrosine kinase inhibitor, affects different pathways involved in angiogenesis, apoptosis or cell proliferation, such as vascular endothelial growth factor (VEGF) receptor types1 (FLT1), 2 (KDR), and 3 (FLT4); platelet-derived growth factor receptors A and B (PDGFRA and PDGFRB); the stem cell factor receptor (cKIT); FMS-like tyrosine kinase 3 (FLT-3), colony-stimulating factor 1 receptor (CSF1R) and glial cell line–derived neurotrophic factor receptor [RE arranged during transfection (RET). The approved and recommended starting dose for sunitinib is 50 mg daily for 4 weeks on-treatment followed by 2 weeks off-treatment (schedule 4/2). Lower starting doses should be considered only if there are significant concerns about potential toxicity. Although TKIs are designed to target specific receptors tyrosin kinases, it is increasingly apparent that many TKIs may display unexpected effects on other kinases and may trigger the appearance of undesirable side effects. The observed incidence of side effects associated with TKIs varies between clinical studies, depending on treatment schedule, dosage, patient characteristics, predisposing factors, secondary diseases, and concurrent administration of other drugs. Moreover, these agents, which do not specifically target tumor cells, are able to act on normal cells, eliciting diverse side effects. Diarrhea and fatigue were the most commonly reported treatment-related adverse. Other adverse events included stomatitis, hand-foot syndrome, hypothyroidism and hypertension, deep venous thromposis and palpitation were a rare side effects.Selected laboratory abnormalities in form of anemia, neutropenia and thrompocytopenia. Fatigue and asthenia represent some of the most frequently encountered sunitinib-related side effects. Approximately 50%% of mRCC patients complain of fatigue.Thyroid function abnormalities have been found in 17of mRCC patients while receiving sunitinib. Hand and Foot syndrome (HFS) developed in 33% of patients. Gastrointestinal side effects, including diarrhea occur in 43% of patients, nausea occurred in 23% of patients, vomiting occurred in 20% of patients and dyspepsia occured in 13% of patients. Sunitinib induced neutropenia and thrombocytopenia in 14% of patients. Anemia occurred with 33% of patients. Most sunitinib toxicities are typically mild to moderate in intensity and are generally manageable with standard medical interventions, without treatment discontinuation or permanent dose reduction. However, the accumulation of several lower-grade side effects can represent a substantial challenge and often require dose/schedule changes and, in some cases, treatment termination.