Chemotherapy in metastatic renal cell carcinoma today? A systematic review Sebastiano Buti a , Melissa Bersanelli a , Angelica Sikokis a , Francesca Maines b , Francesco Facchinetti a , Emilio Bria b , Andrea Ardizzoni a , Giampaolo Tortora b and Francesco Massari b The prognosis of patients affected by metastatic renal cell carcinoma (mRCC) has improved markedly with targeted therapies. Unfortunately, 20–25% of the patients are refractory to treatment at the first response assessment and most patients will acquire drug resistance during the treatment. Moreover, current data on the clinical activity of targeted agents in poor risk or non-clear-cell mRCC patients are inconclusive because of the absence of prospective trials. Therefore, there are still several patients in need of new therapeutic approaches to improve clinical outcomes. Kidney cancer is historically considered resistant to chemotherapy on the basis that the results of phase II trials have not always been promising. We carried out a systematic review of both monochemotherapy and polychemotherapy alone or combined with immunotherapy or targeted agents in mRCC to define the state of the art and to evaluate further clinical research fields. All retrospectives, phase I/dose finding, phase II and phase III studies on chemotherapy in mRCC, published in the literature from January 2003 to November 2012, with at least 20 patients enrolled, were evaluated. Although the results of clinical trials have often been disappointing, in selected cases of mRCC, chemotherapy may have a promising antitumor activity, particularly when there are sarcomatoid differentiation features, or in highly progressive disease where the combination of doxorubicine plus gemcitabine or capecitabine has yielded interesting results. Chemotherapy may play a role in mRCC, whereas targeted agents and immunotherapy have not yielded durable and satisfactory results; further studies are needed. Anti-Cancer Drugs 00:000–000  c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Anti-Cancer Drugs 2013, 00:000–000 Keywords: antineoplastic combined chemotherapy protocols, chemotherapy, kidney cancer, metastatic renal cell carcinoma, renal cell carcinoma a Department of Oncology, University Hospital of Parma, Parma and b Department of Medical Oncology, ‘G.B. Rossi’ Academic Hospital, University of Verona, Verona, Italy Correspondence to Melissa Bersanelli, MD, Department of Oncology, University Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy Tel: + 39 0521 702660/2661; fax: + 39 0521 995448; e-mail: melissa.bersanelli@alice.it Received 15 January 2013 Revised form accepted 13 March 2013 Introduction Although cytotoxic drugs are considered the therapeutic standard for most solid malignancies, renal cancer has traditionally been considered refractory to standard chemotherapy [1,2]. Until 2005, immunotherapy, parti- cularly high-dose interleukin-2 (IL-2) and interferon a (IFN-a), was the only treatment option approved by regulatory authorities for advanced renal cell carcinoma (RCC) [3,4]. Nowadays, targeted therapies involving vascular endothe- lial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways have increased the ther- apeutic options considerably and improved the outcome in metastatic RCC (mRCC) [5–15]. Despite the clinical introduction of these new drugs and possibility of their sequential use, advanced RCC remains incurable in most cases, with a median overall survival (OS) of 22 months [16]. Around 20–25% of metastatic patients, usually called ‘primary resistant’, do not respond to any of the treatments available, leading to a rapidly evolving disease with a very poor prognosis [17]. Furthermore, most, if not all, patients, acquire resistance to antiangio- genic drugs over time even if they show a good initial response [17]. Some of these patients, after receiving three or four lines of targeted therapies, are still fit and potential candidates for further treatment options, not available at the moment. The clinical use of new target drugs is conditional on tumor histology. Except for temsirolimus, approved for the treatment of advanced RCC with non-clear-cell histology, all other new drugs have been recently registered only for the clear cell histological subtype. Therefore, the non-clear-cell histology represents an orphan subgroup in which there is a need for new treatment strategies. Particularly, sarcomatoid differentia- tion, characterized by aggressive biological behavior and a very poor prognosis because of its rapid rate of prolifera- tion, currently represents a histological variant in which immunotherapy failed and chemotherapy showed some antitumor activity [18]. To develop new treatment strategies that can capitalize on different mechanisms of action, nowadays, chemo- therapy could play an interesting role, particularly Review article 1 0959-4973  c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/CAD.0b013e3283609ec1