Renal cell carcinoma tumors are significantly different with respect to their cell type origin, type of genetic mutation, and in turn, responsiveness to different modes of therapy and clinical course. Four hereditary forms of RCC have been identified with specific genetic components: Birt-Hogg-Dube (BHD1 aka Folliculin gene), familial leiomyomatosis and RCC (fumarate hydratase gene), hereditary papillary RCC (c-MET proto-oncogene), and von Hippel–Lindau (VHL gene). The role of VHL gene in RCC has been studied extensively and has resulted in the identification of several new targets for molecular therapies.

Von Hippel–Lindau disease was first described in the medical literature in 1894 in a report describing two siblings with abnormal, bilateral vascular retinal growths [13]. Eugene von Hippel described similar blood vessel tumors in members of one family in 1904 [14]. Arvid Lindau, a Swedish pathologist, described the presence of vascular tumors within the CNS associated with retinal tumors [15]. Since then, additional tumors have been described in the setting of VHL disease, namely clear cell renal cell carcinomas, pheochromocytomas, and pancreatic tumors of the islet cells. Approximately 50 % of patients with VHL disease will develop RCC, commonly after the third decade of life. Elegant genetic mapping studies performed on DNA of von Hippel–Lindau disease patients led to localization of the VHL gene to the short arm of chromosome 3 in 1988 by Seizinger et al. [16]. Analyses of DNA from RCC tumors of patients without VHL disease showed that 33–66 % of sporadic RCC tumors, predominantly clear cell RCC, contain the VHL mutation [17, 18]. The VHL tumor suppressor, VHL protein (pVHL) , has been identified as a regulator of hypoxia-inducible genes based on observation that cells lacking pVHL have abnormally high amounts of hypoxia-inducible mRNA in the presence of normal oxygen levels [19]. It is an indirect regulation by a protein complex containing pVHL that marks hypoxia inducible factor (HIF) with ubiquitin for destruction by proteasomes. Absent or nonfunctional pVHL then leads to over-accumulation of HIF which, in turn, greatly increases transcription of HIF target genes including genes coding for various growth factors [20]. Additionally, HIF has been implemented in facilitating metastatic process through upregulation of the transcription factor TWIST, a master regulator of gastrulation and mesoderm-specification implicated in metastasis of hepatocellular carcinomas [21] as well as downregulation of intercellular adhesion molecules (integrins, E-cadherin) and upregulation of matrix metalloproteinases (MMP2, MMP9) [22]. Understanding of these pathways was crucial for the development of targeted therapy.

As of 2014, there are seven FDA-approved drugs for use in mRCC utilizing four different mechanisms of action. Bevacizumab (Avastin) is a IgG₁ monoclonal antibody able to recognize and bind circulating extracellular vascular endothelial growth factor (VEGF) molecules and thus preventing them from binding to the VEGF receptor on endothelial cells and pericytes. Activation of VEGF receptors initiates a signaling cascade leading to angiogenesis necessary to support tumor cells growth. Axitinib (Inlyta) and Pazopanib (Votrient) are both kinase inhibitors effective against tyrosine kinases associated with VEGF receptors. Sunitinib (Sutent) and Sorafenib (Nexavar) are also kinase inhibitors, but unlike Axitinib and Pazopanib, they have activity against intracellular kinase Raf-1 in addition to activity against tyrosine kinases associated with VEGF and platelet derived growth factor (PDGF) receptors [23]. Temsirolimus (Torisel) and Everolimus (Afinitor) are inhibitors of the mammalian target of rapamycin (mTOR) , a kinase involved in regulation of cell proliferation, survival, and transcription of HIF [24]. In general, targeted therapies are well tolerated with relatively mild side-effects: rashes, hypertension, hand/foot syndrome, and diarrhea [25]. Summary of the seven currently available and FDA approved agents for targeted therapy in mRCC and their performance in initial trials can be found in Table 7.2. Figure 7.1 shows the molecular targets of targeted therapy.

Immunotherapy with cytokines interferon-α and interleukin-2 has been utilized in the treatment of advanced RCC since their clinical trials in early 1980s. The exact mechanism of either of these agents is not fully understood. While IFN-α has some antiproliferative and direct antitumor properties [26], IL-2 has a wide-ranging stimulatory effect on the immune system including both T and B cells, monocytes, macrophages, and natural killer cells leading to tumor cell cytotoxicity [27].

Initial clinical trials of IL-2 showed response rates of over 30 %, but subsequent studies had lower response rates between 15 and 23 % [28, 29]. Most importantly, 7–9 % of patients treated with HD IL-2 had a durable complete response. Median duration of completed responses was not reached at the time of analysis, but have been estimated to be >80 months with 20 % patients surviving for 10 years following their treatment [28]. The efficacy of Il-2 appears to be dose-related as suggested by the results of a three arm trial with high IV dose, low IV dose, and SQ dose of IL-2 with response rates of 15, 10, and 8 %, respectively [30]. Unfortunately, IL-2 in high doses is very poorly tolerated and needs to be administered in an inpatient setting, preventing its wide spread use in all patients with mRCC despite its ability to induce a durable complete response. Such a response has not been seen with any targeted agent yet developed.

Until the advent of targeted therapy, IFN-α had been the agent of choice in the initial treatment of mRCC. Its response rates are generally lower (10–15 %) than those of IL-2 and durable complete responses are quite rare at less than 2 % [31, 32]. Unlike IL-2, IFN-α is relatively well tolerated and easily administered in the outpatient setting. Even though it has been shown to be inferior in terms of survival to the new mTOR and tyrosine kinase inhibitors in several comparative trials, it is still used in combination with VEGF monoclonal antibodies (Bevacizumab) [33, 34].

Renal cell carcinoma remains the deadliest of all genitourinary cancers. It is a complex disease with highly variable natural history and biological behavior. Approximately 30–40 % of newly diagnosed patients with RCC have evidence of metastatic disease. Additionally, 20–40 % of patients who initially presented with localized disease will develop metastases, frequently within 2 years. The majority of metastatic cases (up to 90 %) develop in the setting of clear cell RCC [35].

Prior to the advent of immunotherapy in early 1990s, the prognosis of patients with metastatic renal cell carcinoma (mRCC) was abysmal with a 10-year survival being virtually nonexistent. Introduction of high dose interleukin-2 therapy (FDA approved for treatment of advanced RCC in 1992) created a breakthrough in the management of advanced RCC. The overall response rates were between 21 and 23 % with durable complete responses seen in only 5–7 % of patients. Historically, the role of surgery in the form of either a cytoreductive nephrectomy or metastasectomy in this setting was purely palliative for cases of persistent hematuria, intractable pain, paraneoplastic manifestations, or constitutional symptoms. With the advent of immunotherapy, debulking of the primary tumor with cytoreductive nephrectomy has been shown to offer a survival benefit in a selected patient population and is now considered the standard of care [36]. However, high dose IL-2 therapy has a long list of specific toxicities related to hyperstimulation of the immune system ranging from relatively mild flu-like symptoms to life-threatening cardiovascular toxicities. These are similar to those seen in sepsis and septic shock [37]. There is a predominate vascular leak syndrome characterized by a widespread capillary leakage leading to a drop in systemic vascular resistance and intravascular volume. This can lead to a decrease in end-organ perfusion, renal insufficiency with oligouria and pulmonary edema [38]. Admission to an intensive care unit is common practice when administering IL-2.

The toxicities of high dose IL-2 treatment created a need for a prognostic model that would identify patients able to withstand the treatment and benefit from it based on clinical features of their disease. One such model was developed and published in 1999 from the Memorial Sloan-Kettering Cancer Center based on data obtained from 24 clinical trials totaling 670 patients with mRCC treated between 1975 and 1996. Multivariate analysis of numerous patient characteristics identified five pretreatment clinical features of mRCC associated with shorter survival: Karnofsky performance status <80 %, high serum lactate dehydrogenase (>1.5 times the upper limit of normal), low hemoglobin (below the lower limit of normal), elevated corrected plasma calcium levels (>10 mg/dl), and absence of prior nephrectomy. The mean overall survival was found to correlate strongly with the number of adverse prognostic factors [39]. The MSKCC model was later found to be predictive of survival in a dataset of 353 patients from Cleveland Clinic [40] and remains widely used in clinical practice today, helping to guide clinical decisions in the treatment of mRCC patients.