Anti-Tumour Treatment Targeted therapies and complete responses in first line treatment of metastatic renal cell carcinoma. A meta-analysis of published trials Roberto Iacovelli a,⇑ , Daniele Alesini a , Antonella Palazzo a , Patrizia Trenta a , Matteo Santoni b , Laura De Marchis a , Stefano Cascinu b , Giuseppe Naso a , Enrico Cortesi a a ‘‘Sapienza’’ University of Rome, Department of Radiology, Oncology and Human Pathology, Viale Regina Elena 324, 00161 Rome, Italy b Polytechnic University of the Marche Region, Department of Medical Oncology, Piazza Roma 22, 60121 Ancona, Italy article info Article history: Received 20 March 2013 Received in revised form 30 August 2013 Accepted 3 September 2013 Keywords: Antiangiogenic agents Metastatic renal cells cancer Complete response Sunitinib Sorafenib Pazopanib Bevacizumab Cytokines Interferon abstract Antiangiogenic agents (AAs) have reported grater efficacy compared to interferon. Despite these advances, radiological complete response to therapy is rare. We meta-analyzed the incidence of complete response in patients treated with AAs and in controls in main randomized clinical trials for first-line ther- apy in metastatic renal cell carcinoma. PubMed was reviewed for phase II–III randomized clinical trials with AAs vs. non-AAs in patients with good or intermediate prognosis. We calculated the relative risk of events in patients assigned to AAs com- pared to control. Five RCTs were found; four were phase III and one was phase II. A total of 2747 patients was valuable for final analysis and randomized to receive AAs or control. Patients in the control-group had interferon (85%) or placebo (15%); patients in the AAs-group received bevacizumab (48%), sunitinib (26%), pazopa- nib (20%) or sorafenib (6%). The incidence of complete response in patients treated with AAs was 2.0% (95% CI, 1.2–2.8) compared to 1.4% (95% CI, 0.7–2.1) in the control arm. Comparing the different type of AAs, the incidence of com- plete response was 2.5% (95% CI, 1.2–3.8) in the bevacizumab group and 1.6% (95% CI, 0.1–2.5) in the TKIs group. The relative risk to have a complete response was 1.52 (95% CI, 0.85–2.73; p = 0.16) in patients treated with AAs compared to controls; this was found higher in patients treated with TKIs compared to bevacizumab. The complete response is a rare event in metastatic kidney tumor, even if AAs reported greater efficacy in terms of progression-free survival and of overall response rate, they did not increase the curative rate of metastatic disease. Probably, some biologic factors other than angiogenesis may influence the com- plete response in this disease. Ó 2013 Elsevier Ltd. All rights reserved. Introduction During the past few years, therapy for metastatic renal cell cancer (mRCC) has significantly changed due to the introduction into clin- ical practice of several different agents that have radically modified the natural history of this pathology. This ‘‘revolution’’ began in the first Nineties with the approval of cytokine-based therapy – mostly Interleukin 2 (IL2) and Interferon alpha (IFN) – for mRCC [1]. In fact, the introduction of immunotherapy was a crucial turning point for the treatment of this neoplasia, giving medical oncologists an important tool for the management of this disease. From the first applications of immunotherapies, it was clear that complete response (CR) was associated with major benefits in terms of progression-free survival (PFS) and overall survival (OS). However, few metastatic patients achieved CR after immuno- therapy [2,3]. During the last ten years, there have been many other active drugs approved for the treatment of metastatic kidney cancer. In most cases, these are agents that target neoplastic neo-angiogene- sis by directly blocking the vascular endothelial growth factor (VEGF; e.g., bevacizumab) [4–6] or its receptor (e.g., tyrosine-ki- nase inhibitors; TKIs) [7–10]. These agents have shown greater activity, in terms of PFS, compared to immunotherapy, specifically when compared to IFN. However, a clinically relevant increase in CRs was not reported and the role of antiangionenic agents (AAs) in increasing the curability of this cancer remains unclear. We performed a meta-analysis of published reports about AA versus 0305-7372/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctrv.2013.09.003 ⇑ Corresponding author. Address: Department of Radiological, Oncological and Anatomo-Pathological Sciences, ‘‘Sapienza’’ University of Rome, Viale Regina Elena 324, 00161 Rome, Italy. Tel.: +39 0649970408; fax: +39 064463686. E-mail addresses: roberto.iacovelli@alice.it, roberto.iacovelli@uniroma1.it (R. Iacovelli). Cancer Treatment Reviews 40 (2014) 271–275 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv