Curr Urol Rep (2015) 16:3 DOI 10.1007/s11934-014-0478-2
KIDNEY DISEASES (G CIANCIO, SECTION EDITOR)
Recent Aspects of Sunitinib Therapy in Patients with Metastatic Clear-Cell Renal Cell Carcinoma: a Systematic Review of the Literature Daniele Minardi & Luigi Quaresima & Matteo Santoni & Maristella Bianconi & Mario Scartozzi & Stefano Cascinu & Giovanni Muzzonigro
# Springer Science+Business Media New York 2015
Abstract Sunitinib is an orally available inhibitor of multiple tyrosine-kinase receptors approved for the treatment of advanced clear-cell renal cell carcinoma (ccRCC), a disease which has habitually had a very poor patient survival rate. Although it has become the most widely used drug for this disease, it remains not completely clear the best treatment strategy with these agent. The aim of this review is to highlight the most recent and interesting aspects of the research on treatment of advanced ccRCC with sunitinib and eventually determine alternative treatment schedule to reduce the incidence of side effects; we also wanted to review recent biomarkers able to predict response to therapy and also to point out the mechanism of acquired resistance to this drug. Keywords VEGF . Clear-cell renal cell carcinoma . Sunitinib . Resistance . Biomarkers . Therapy
Introduction Renal cell carcinoma (RCC) represents the 2–3 % of all malignant tumors in adults, and the clear-cell RCC (ccRCC) is its most frequent histological subtype [1]. So far, metastatic RCC
This article is part of the Topical Collection on Kidney Diseases D. Minardi (*) : L. Quaresima : G. Muzzonigro Department of Clinic and Specialistic Sciences - Urology, Polytechnic University of the Marche Region - Azienda Ospedaliero - Universitaria Ospedali Riuniti, via Conca, 71, 60131 Ancona, Italy e-mail: [email protected] M. Santoni : M. Bianconi : M. Scartozzi : S. Cascinu Department of Medical Oncology, Polytechnic University of the Marche Region - Azienda Ospedaliero - Universitaria Ospedali Riuniti, Ancona, Italy
(mRCC) was considered a cancer with a poor prognosis: conventional therapies, such as chemotherapy and radiation therapy, are not effective; only few patients benefit from immunotherapy [2]. A characteristic of RCC is its high vascularity, which is attributed to the alteration of the Von Hippel–Lindau (VHL) tumor suppressor gene, leading to the accumulation of transcription factors such as hipoxia-inducible factor 1 alpha and 2 alpha (HIF-1α, HIF-2α) that mediate the overexpression of vascular endothelial growth factor (VEGF) [3]. According to this rationale, actually VEGF inhibitors, including targeted therapy with tyrosine-kinase inhibitors (TKIs), angiogenesis inhibitor, and mammalian target of rapamycin (mTOR) inhibitors are the standard of care for mRCC recommended in most guidelines worldwide [4]. Sunitinib is a small-molecule multiple receptor TKI, orally administrated, with activity against the stem cell-factor receptor (Kit) and platelet-derived growth factor (PDGFR), VEGF receptor (VEGFR), glial cell line-derived neurotrophic factor receptor (rearranged during transfection [RET]), colony-stimulating factor-1 receptor (CSF1R), and Fms-like tyrosine-kinase-3 receptor (FLT3) [5, 6]. Sunitinib (sunitinib malate, Sutent®) is approved worldwide for the first-line treatment of advanced ccRCC and has reported significant initial objective response rates up to 47 % [7, 8]; on the other hand, a number of patients with metastatic ccRCC exhibited no clinical benefits from sunitinib treatment. For this reason, the identification of prognostic and predictive biomarkers associated with a longer progression-free survival and a sunitinib response, respectively, is required to enhance the outcome of patients with advanced ccRCC by specific therapies. Moreover, in most cases, this therapeutic option represents no definitive cure. Even in cases that initially respond well to sunitinib, tumor regrowth occurs owing to chemoresistance [9]. This article reviews the current state of the art concerning sunitinib clinical outcomes related to the schedule, the
3
Page 2 of 7
possible role of prognostic, and the predictive biomarkers in order to optimize sunitinib response and to highlight the mechanisms involved in the resistance to this drug.
Standard and Alternative Dosing Schedules of Sunitinib and Response Rate In 2007, Motzer et al. published the results of a double-blind randomized trial of 750 patients with metastatic RCC aimed to compare sunitinib vs interferon-α (IFN-α) as a first-line therapy [10]. In this study, patients treated in the sunitinib arm showed a significantly improved median progression-free survival (PFS) of 11 vs 5 months and a slightly significant improved overall survival (OS) of 26.4 vs 21.8 months (p=0.051), although this difference was likely to be underestimated due to significant crossover from IFN-α to sunitinib after unblinding. Concerning the adverse events (AEs), sunitinib was associated with a higher treatment-related toxicity than IFN-α. The most common grade 3 or 4 treatment-related AEs were hypertension (12 %), fatigue (11 %), diarrhea (9 %), and hand–foot syndrome (9 %) [8, 10]. In the sunitinib open-access program, 8 % of patients discontinued sunitinib due to serious AEs, with a further 30 % of patients who experienced dose reductions due to toxicity [11]. The high incidence of dose reduction and treatment discontinuation correlated to sunitinib treatment leads scientists to investigate the efficacy and safety of alternative schedules of sunitinib [12]. Among alternative schedules, the 2 weeks on/ 1 week off regimen seems to be a potential candidate to become the novel standard schedule of sunitinib. In 2014, Atkinson et al. have presented the results of a single-center retrospective analysis on 187 mRCC patients treated with standard and/or alternative sunitinib schedules. During treatment, 53 % of patients started and continued on the standard schedule, while 47 % began or were transitioned to alternative schedules (82 % received the 2 weeks on/1 week off regimen). The median PFS was 4.3 months in patients on 4/2 schedule and 14.5 months in those on alternative schedules (p
KIDNEY DISEASES (G CIANCIO, SECTION EDITOR)
Recent Aspects of Sunitinib Therapy in Patients with Metastatic Clear-Cell Renal Cell Carcinoma: a Systematic Review of the Literature Daniele Minardi & Luigi Quaresima & Matteo Santoni & Maristella Bianconi & Mario Scartozzi & Stefano Cascinu & Giovanni Muzzonigro
# Springer Science+Business Media New York 2015
Abstract Sunitinib is an orally available inhibitor of multiple tyrosine-kinase receptors approved for the treatment of advanced clear-cell renal cell carcinoma (ccRCC), a disease which has habitually had a very poor patient survival rate. Although it has become the most widely used drug for this disease, it remains not completely clear the best treatment strategy with these agent. The aim of this review is to highlight the most recent and interesting aspects of the research on treatment of advanced ccRCC with sunitinib and eventually determine alternative treatment schedule to reduce the incidence of side effects; we also wanted to review recent biomarkers able to predict response to therapy and also to point out the mechanism of acquired resistance to this drug. Keywords VEGF . Clear-cell renal cell carcinoma . Sunitinib . Resistance . Biomarkers . Therapy
Introduction Renal cell carcinoma (RCC) represents the 2–3 % of all malignant tumors in adults, and the clear-cell RCC (ccRCC) is its most frequent histological subtype [1]. So far, metastatic RCC
This article is part of the Topical Collection on Kidney Diseases D. Minardi (*) : L. Quaresima : G. Muzzonigro Department of Clinic and Specialistic Sciences - Urology, Polytechnic University of the Marche Region - Azienda Ospedaliero - Universitaria Ospedali Riuniti, via Conca, 71, 60131 Ancona, Italy e-mail: [email protected] M. Santoni : M. Bianconi : M. Scartozzi : S. Cascinu Department of Medical Oncology, Polytechnic University of the Marche Region - Azienda Ospedaliero - Universitaria Ospedali Riuniti, Ancona, Italy
(mRCC) was considered a cancer with a poor prognosis: conventional therapies, such as chemotherapy and radiation therapy, are not effective; only few patients benefit from immunotherapy [2]. A characteristic of RCC is its high vascularity, which is attributed to the alteration of the Von Hippel–Lindau (VHL) tumor suppressor gene, leading to the accumulation of transcription factors such as hipoxia-inducible factor 1 alpha and 2 alpha (HIF-1α, HIF-2α) that mediate the overexpression of vascular endothelial growth factor (VEGF) [3]. According to this rationale, actually VEGF inhibitors, including targeted therapy with tyrosine-kinase inhibitors (TKIs), angiogenesis inhibitor, and mammalian target of rapamycin (mTOR) inhibitors are the standard of care for mRCC recommended in most guidelines worldwide [4]. Sunitinib is a small-molecule multiple receptor TKI, orally administrated, with activity against the stem cell-factor receptor (Kit) and platelet-derived growth factor (PDGFR), VEGF receptor (VEGFR), glial cell line-derived neurotrophic factor receptor (rearranged during transfection [RET]), colony-stimulating factor-1 receptor (CSF1R), and Fms-like tyrosine-kinase-3 receptor (FLT3) [5, 6]. Sunitinib (sunitinib malate, Sutent®) is approved worldwide for the first-line treatment of advanced ccRCC and has reported significant initial objective response rates up to 47 % [7, 8]; on the other hand, a number of patients with metastatic ccRCC exhibited no clinical benefits from sunitinib treatment. For this reason, the identification of prognostic and predictive biomarkers associated with a longer progression-free survival and a sunitinib response, respectively, is required to enhance the outcome of patients with advanced ccRCC by specific therapies. Moreover, in most cases, this therapeutic option represents no definitive cure. Even in cases that initially respond well to sunitinib, tumor regrowth occurs owing to chemoresistance [9]. This article reviews the current state of the art concerning sunitinib clinical outcomes related to the schedule, the
3
Page 2 of 7
possible role of prognostic, and the predictive biomarkers in order to optimize sunitinib response and to highlight the mechanisms involved in the resistance to this drug.
Standard and Alternative Dosing Schedules of Sunitinib and Response Rate In 2007, Motzer et al. published the results of a double-blind randomized trial of 750 patients with metastatic RCC aimed to compare sunitinib vs interferon-α (IFN-α) as a first-line therapy [10]. In this study, patients treated in the sunitinib arm showed a significantly improved median progression-free survival (PFS) of 11 vs 5 months and a slightly significant improved overall survival (OS) of 26.4 vs 21.8 months (p=0.051), although this difference was likely to be underestimated due to significant crossover from IFN-α to sunitinib after unblinding. Concerning the adverse events (AEs), sunitinib was associated with a higher treatment-related toxicity than IFN-α. The most common grade 3 or 4 treatment-related AEs were hypertension (12 %), fatigue (11 %), diarrhea (9 %), and hand–foot syndrome (9 %) [8, 10]. In the sunitinib open-access program, 8 % of patients discontinued sunitinib due to serious AEs, with a further 30 % of patients who experienced dose reductions due to toxicity [11]. The high incidence of dose reduction and treatment discontinuation correlated to sunitinib treatment leads scientists to investigate the efficacy and safety of alternative schedules of sunitinib [12]. Among alternative schedules, the 2 weeks on/ 1 week off regimen seems to be a potential candidate to become the novel standard schedule of sunitinib. In 2014, Atkinson et al. have presented the results of a single-center retrospective analysis on 187 mRCC patients treated with standard and/or alternative sunitinib schedules. During treatment, 53 % of patients started and continued on the standard schedule, while 47 % began or were transitioned to alternative schedules (82 % received the 2 weeks on/1 week off regimen). The median PFS was 4.3 months in patients on 4/2 schedule and 14.5 months in those on alternative schedules (p
