Renal cell carcinoma (RCC) has historically been regarded as highly resistant to systemic therapy-indeed, it has been considered among the most resistant of all neoplasms. A review of the state of affairs in the treatment of metastatic RCC 20 years ago provides important insight into the formidable difficulty in developing active agents for this disease. In a lecture at the Memorial Sloan-Kettering Cancer Center (MSKCC) in 1984, Dr. Alan Yagoda summarized the almost nonexistent status of systemic therapy for metastatic RCC, noting, "At this time, there appears to be no single agent, hormonal manipulation or combination drug regimen which is useful in controlling disseminated renal cancer..."[1] This statement was based on the results of multiple trials demonstrating the relative futility of both cytotoxic and hormonal therapies. More than 20 agents had already been studied at that time, with some of the more notable ineffective therapeutics including vinblastine(Drug information on vinblastine), the nitrosoureas, dactinomycin(Drug information on dactinomycin) (Cosmegen), etoposide, lomustine (CeeNU), flutamide, and progesterone(Drug information on progesterone) agonists.[1]
Over the past 20 years, substantial progress has been made in both understanding and treating metastatic RCC. This paper will discuss the most important of these advances, including a brief focus on the evolution of cytokine treatment in the late 1980s and early 1990s and a comprehensive review of the more recent development of novel targeted therapies. In addition, we will review some of the important basic science discoveries that have provided insight into the pathogenesis of RCC and led to the identification of the targets of these new drugs.
Introduction and Epidemiology
It is estimated that in the year 2006, nearly 39,000 new cases of renal cell carcinoma (RCC) will be diagnosed in the United States. With a 1.6:1.0 male-to-female ratio, RCC ranks 7th in cancer incidence among American men and 12th among American women, comprising 2% to 3% of all cancer cases diagnosed in the United States each year.[2] In addition, RCC contributes annually to over 13,000 American[2] and 100,000 worldwide deaths.[3] Furthermore, there has been a steady 3% annual rise in the incidence of RCC in both the United States and Europe over the past 3 decades.[4] This trend cannot be entirely explained by the shift toward earlier diagnoses with the increasing use of radiographic diagnostic testing.[4]
There are several distinct histologic types of RCC, each originating from different locations within the renal epithelia. The majority (≥ 75%) of cases are of the clear cell (conventional) type; other renal cell histologies include type I (5%) and type II (10%) papillary (chromophilic), chromophobic (5%), oncocytoma (< 5%), and collecting duct (Bellini's duct) tumors (< 1%).[5,6] As is the case with many malignancies, each histologic subtype exhibits a different clinical behavior and is associated with distinct mutations.
Despite the earlier detection of renal cell malignancies by imaging studies performed for the work-up of unrelated complaints, approximately 30% of patients will still have metastatic disease at diagnosis. Of the remaining 70% who present with localized disease, up to one-third will go on to develop metastases. For patients with metastatic disease, the median survival is approximately 1 year from diagnosis, and only 10% will survive 5 years.[7,8] Such statistics reflect the aggressive nature of metastatic RCC, and underscore the historical lack of effective treatments.
To improve outcomes for advanced RCC, many different treatment approaches have been investigated. While cytoreductive radical nephrectomy[9,10] and metastasectomy[11,12] are an important part of management and can even prolong patients' lives, these procedures are rarely curative.[11] Furthermore, patients with widespread disease are often not candidates for these surgical options. Ideally, an effective systemic therapy is needed to provide long-term disease control for metastatic RCC.
Unfortunately, in contrast to other aggressive malignancies, RCC is highly resistant to cytotoxic chemotherapy. Many such agents have been explored in clinical trials but none has demonstrated sufficient efficacy to justify the associated toxicities.[5] Hormonal therapies have been similarly ineffective,[5] and no member of either of these two classes has been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic renal carcinomas. Until recently, the mainstay of treatment for patients with metastatic disease has consisted of immune modifying agents, such as interleukin (IL)-2 (Proleukin) and interferon (IFN)-alpha.
Cytokine Therapy
The initial use of cytokine therapy for metastatic RCC was based on several findings that suggested an ability of the immune system to regulate renal tumor growth. Such evidence included observations of patients with long disease-free intervals following nephrectomy,[13] disease stabilization for 1 to 2 years without any treatment,[14] and spontaneous tumor regression in a minority of patients.[15,16]
In general, the response rates to IL-2 and IFN-alpha range from 10% to 20%, with a median survival of approximately 12 months.[5] Although complete responses (CR) are rare with IFN-alpha, at least two studies have shown this cytokine to provide a survival advantage compared with either placebo or cytotoxic chemotherapy.[17,18] Unlike IFN-alpha, high-dose IL-2 can induce a durable CR in about 5% of patients.[19] For those who achieve a CR, the median duration of response is about 40 months, with some responses lasting up to 6 years.[20] On the basis of these results, high-dose IL-2 was approved in the United States, and IFN-alpha in parts of Europe, for the treatment of advanced RCC.
Unfortunately, these immunomodulating agents are not without toxicities, and high-dose IL-2 is generally administered with intensive-care unit support. In addition, the clinical benefit of both agents, particularly IL-2, is restricted to a relatively small group of highly selected patients. Furthermore, randomized trials have failed to demonstrate a superior median survival or progression-free survival with high-dose therapy, compared with low-dose or combination cytokine treatment.[21,22] Attempts to improve upon the modest response rates afforded by cytokine therapy by adding cytotoxic chemotherapy or combining IFN with IL-2 have also been disappointing. These strategies generally lead to increased toxicity and do not improve outcomes.[23] Finally, until recently, effective treatment options were lacking for cytokine-refractory patients, since switching to an alternate cytokine therapy was shown to provide no benefit.[24]
Pathobiology and Identification of Therapeutic Targets
Association of VHL Disease With Clear Cell RCC
As part of his two-hit hypothesis regarding tumor-suppressor genes, Knudson theorized that sporadic cases of a particular type of cancer should involve the same gene as those associated with a hereditary syndrome.[25] With the genetic syndrome, patients are borrn with a germ-line mutation or deletion in one allele and then acquire the second "hit" (usually) early in life. Sporadic tumors occur at older ages because sufficient time is required for both alleles to become mutated.
Von-Hippel-Lindau (VHL) disease is an inherited, autosomal, dominant syndrome characterized by a variety of benign and malignant tumors, most notably retinal angiomas, hemangioblastomas of the central nervous system, pheochromocytomas, renal and pancreatic cysts, and clear cell RCC. In the early 1990s, the VHL gene was successfully cloned, and in accordance with Knudson's theory, alterations in this gene were found in many cases of sporadic clear cell RCC in addition to patients with VHL disease.[26] In particular, somatic mutations occur in about 50% and hypermethylation in an additional 10% to 20% of clear cell RCC cases.[27]
VHL Protein Function
The protein product of the VHL gene is a polyubiquitin complex (pVHL) responsible under normoxic conditions for ubiquitinating the transcription factor, hypoxia-inducible factor (HIF)-1-alpha, which marks it for proteasomal degradation.[27] This process depends upon oxygenated conditions, because pVHL can only bind to HIF-1 after hydroxylation of one of its prolyl residues. Under hypoxic conditions, hydroxylation of HIF-1-alpha does not occur, prohibiting pVHL from binding. Instead of being degraded, HIF-1-alpha can then translocate to the nucleus and attach to HIF-1-beta to form the active HIF-1 complex.
In the nucleus, active HIF-1 acts as a transcription factor for several hypoxia-responsive genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), the epidermal growth factor receptor (EGFR), glucose transporters (eg, GLUT-1), transforming growth factor-alpha (TGF-alpha, ligand for EGFR), and erythropoietin(Drug information on erythropoietin).[27] Many of these proteins are involved in angiogenesis, survival, pH regulation, and glucose metabolism. The absence of a functional VHL protein in the inherited and sporadic forms of clear cell carcinoma simulates hypoxia with resultant constitutive upregulation of these genes.
In addition to regulation by pVHL, recent studies have shown that HIF-1 activity is also affected by the EGFR-phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR pathway. Binding of TGF-alpha to EGFR results in stimulation of the PI3K-AKT-mTOR pathway, leading to increased translation of HIF-1.[28] Since EGFR and TGF-alpha are also under transcriptional regulation by HIF-1-alpha, such integration creates a positive feedback loop, ensuring an adequate response to hypoxic conditions. Furthermore, signaling through EGFR-PI3K-AKT-mTOR can also result in increased VEGF levels through a mechanism independent of HIF [29].
The Ras-Raf-MEK-ERK pathway may also regulate HIF-1-alpha.[30] Thus, in clear cell RCC, mutations in VHL and genes of distinct but interrelated pathways results in upregulation of proteins integral to tumor growth and angiogenesis. Dissection of the complex relationships between these pathways has led to the identification of new targets for RCC treatment. Based on such advances, drugs that attack these targets have been developed. These agents have recently demonstrated efficacy in clinical trials and are beginning to change the standard of care for metastatic RCC.
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