US estimates for 2007 indicate that 51,190 individuals were diagnosed with cancer of the kidney and renal pelvis, and 12,890 individuals died from the disease. 1 Kidney and renal pelvis cancer is the 3rd most common genitourinary cancer after prostate cancer and bladder cancer. 2 The median age of individuals at diagnosis was 65 years; the median age of individuals at death was 71 years. 1 Estimates predict that approximately 240,266 Americans with a history of cancer of the kidney and renal pelvis were alive as of January 1, 2004. 1 5-year disease survival has improved from a rate of 50.9% in 1975-1977 to 65.7% in 1996-2003. 3 National Cancer Institute. SEER cancer statistics fact sheet: Cancer of the kidney and renal pelvis. Available at http://seer.cancer.gov/statfacts/html/kidrp.html?statfacts_page=kidrp.html&x=22&y=16. Accessed February 8, 2008. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin . 2007;57:43-66. Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2004. Bethesda, MD: National Cancer Institute; 2007. Available at: http://seer.cancer.gov/csr/1975_2004/.
The incidence rate of RCC has steadily increased over time, from 7.1 per 100,000 individuals in 1975 to 13.1 per 100,000 individuals in 2004. 1 The increasing incidence may be partially explained by the greater numbers of asymptomatic tumors that are being detected with noninvasive imaging modalities (ie, computed tomography, magnetic resonance imaging). The mortality rate of RCC has remained relatively stable over time, at 3.6 per 100,000 individuals in 1975 and 4.1 per 100,000 individuals in 2004. Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2004. Bethesda, MD: National Cancer Institute; 2007. Available at: http://seer.cancer.gov/csr/1975_2004/.
Estimates for 2007 indicate that kidney and renal pelvis cancer accounts for 3.5% of all cancers in the United States. 1 Kidney and renal pelvis cancer is the 7th most common cancer in men and the 9th most common cancer in women. NHL: non-Hodgkin’s lymphoma. 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin . 2007;57:43-66.
Surgical resection of the kidney is called nephrectomy. During radical nephrectomy, the entire kidney is removed. During partial nephrectomy, only the cancerous portion of the kidney is removed, along with a margin of healthy tissue. Surgery is potentially curative for patients with early-stage RCC (ie, stage I, II, III), but not for those with metastatic disease. Patients who undergo surgery must be carefully followed after the procedure, as 25%-50% will develop disease recurrence. 1 Surgery may play a limited role in metastatic disease as a means to provide palliation or to enhance disease control in combination with other treatment modalities. 1. Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and m anagement of recurrent disease. Urol Clin North Am . 2003;30 :843-852.
Unfortunately, because RCC is clinically silent for much of its natural history, many individuals present with unresectable disease, metastatic disease, or locally advanced RCC prone to recurrence. 1,2 Surgery is not an option for cure in these individuals. Several other treatment options exist, but not all are effective. In particular, advanced RCC is extremely resistant to radiotherapy and chemotherapy. National Cancer Institute. SEER cancer statistics fact sheet: Cancer of the kidney and renal pelvis. Available at http://seer.cancer.gov/statfacts/html/kidrp.html?statfacts_page=kidrp.html&x=22&y=16. Accessed February 8, 2008. Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and m anagement of recurrent disease. Urol Clin North Am . 2003;30:843-852.
RCC is regarded as radioresistant. Radiotherapy has been shown to be ineffective at prolonging survival when administered either before or after surgery in patients with resectable RCCs. 1-3 Radiotherapy may provide some benefit for painful bone metastases, brain metastases, or painful recurrences in the renal bed in individuals with metastatic RCC. 4 1. Finney R. The value of radiotherapy in the treatment of hypernephroma--a clinical trial. Br J Urol. 1973;45:258-269. 2. Juusela H, Malmio K, Alfthan O, Oravisto KJ. Preoperative irradiation in the treatment of renal adenocarcinoma. Scand J Urol Nephrol. 1977;11:277-281. 3. Stein M, Kuten A, Halpern J, Coachman NM, Cohen Y, Robinson E. The value of postoperative irradiation in renal cell cancer. Radiother Oncol. 1992;24:41-44. 4. Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and m anagement of recurrent disease. Urol Clin North Am. 2003;30:843-852.
RCC has intrinsic resistance to conventional chemotherapy, typically resulting in response rates ≤ 6%. 1 As such, this treatment modality is not used to manage individuals with RCC. 1. Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol . 2000;163:408-417.
Several features of RCC tumors support the notion that it is an immunogenic disease, as detailed above. 1-7 As such, immunotherapy has long been the principal treatment modality for managing advanced RCC. 8 de Riese W, Goldenberg K, Allhoff E, et al. Metastatic renal cell carcinoma (RCC): spontaneous regression, long-term survival and late recurrence. Int Urol Nephrol . 1991;23:13-25. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996;335:865-875. Whang YE, Godley PA. Renal cell carcinoma. Curr Opin Oncol . 2003;15:213-216. Schoof DD, Terashima Y, Peoples GE, et al. CD4+ T cell clones isolated from human renal cell carcinoma possess the functional characteristics of Th2 helper cells. Cell Immunol . 1993;150:114-123. Kowalczyk D, Skorupski W, Kwias Z, Nowak J. Flow cytometric analysis of tumour-infiltrating lymphocytes in patients with renal cell carcinoma. Br J Urol . 1997;80:543-547. van den Hove LE, Van Gool SW, Van Poppel H, et al. Phenotype, cytokine production and cytolytic capacity of fresh (uncultured) tumour-infiltrating T lymphocytes in human renal cell carcinoma. Clin Exp Immunol . 1997;109:501-509. Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev . 2005;(1):CD001425. Bukowski RM. Immunotherapy in renal cell carcinoma. Oncology . 1999;13:801-810.
Current immunotherapies for RCC include recombinant human interleukin-2 (IL-2) and recombinant human interferon -2b (IFN- ), both of which can be used either alone or in combination. IL-2 is a cytokine that stimulates the growth of immune cells and activates those cells to destroy tumor cells. IFN- is a protein produced by white blood cells in response to infection or foreign invasion. This cytokine increases antigen presentation on the surface of cancer cells, thereby increasing their susceptibility to attack by the immune system. Both agents are associated with considerable toxicity, namely flu-like symptoms, nausea, diarrhea, and, in the case of IFN- , fatigue and depression.
A recent meta-analysis of 58 randomized trials of immunotherapy conducted in 6880 patients with advanced RCC helps illuminate the effectiveness of this treatment modality. 1 The combined response rate of immunotherapy versus active controls was 12.4% vs 2.4%, while the mean overall survival was 13 months vs 9.5 months. Of the 2 agents, IFN- appeared to be somewhat more effective in that it increased overall survival by an average of 3.8 months, decreased the risk of 1-year mortality by 44%, and decreased the risk of 2-year mortality by 26%. Although high-dose IL-2 was associated with response rates as high as 23%, this failed to translate into a survival advantage compared with active controls. Given this very modest level of efficacy in advanced RCC as a whole, the toxicity of immunotherapy often outweighs the potential benefits. It should be noted that select subgroups of patients appear to derive better benefit with immunotherapy than others. ORR: overall response rate; OS: overall survival. 1. Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev . 2005;(1):CD001425.
Individuals with metastatic RCC have a very poor prognosis, with a 5-year survival rate of only 9.5%. 1 This poor outlook stems from the fact that, up until recently, these individuals had very few treatment options. Surgery is not a potential option for cure, chemotherapy and radiotherapy play little to no role in treatment, and immunotherapy produces limited benefit at the expense of considerable toxicity. These significant unmet treatment needs for patients with advanced RCC drove investigators to acquire a greater understanding of the biologic basis of renal oncogenesis in order to guide rational approaches to treatment. 1. National Cancer Institute. SEER cancer statistics fact sheet: Cancer of the kidney and renal pelvis. Available at http://seer.cancer.gov/statfacts/html/kidrp.html?statfacts_page=kidrp.html&x=22&y=16. Accessed February 8, 2008.
Angiogenesis has been defined as a key determinant in the pathophysiology of RCC. 1 RCC tumors are among the most vascularized of all solid tumors. 2 Izawa JI, Dinney CP. The role of angiogenesis in prostate and other urologic cancers: a review. CMAJ . 2001;164:662-670. Cristofanilli M, Charnsangavej C, Hortobagyi GN. Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discov . 2002;1:415-426.
Vascular endothelial growth factor (VEGF) is a key growth factor involved in angiogenesis. 1,2 VEGF mRNA expression correlates with vascularization, and VEGF is overexpressed in the majority of patients with clear-cell RCC. Other growth factors that contribute to angiogenesis and oncogenesis include platelet-derived growth factor (PDGF) and epithelial growth factor (EGF), among others. Cristofanilli M, Charnsangavej C, Hortobagyi GN. Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discov . 2002;1:415-426. De Mulder PH. Targeted therapy in metastatic renal cell carcinoma. Ann Oncol . 2007;18:ix98-102.
The above figure depicts a simplified overview of some key steps in tumor angiogenesis. 1 First, tumor cells secrete proangiogenic factors (e.g., VEGF) that bind to receptors on endothelial cells of pre-existing blood vessels. These interactions lead to the release of proteolytic enzymes (e.g., matrix metalloproteinases) that digest through the basement membrane and extracellular matrix. These breaches enable growth factors to reach and activate endothelial cells that migrate toward the tumor. Integrin molecules also help to pull newly formed blood vessels toward the tumor. The endothelial cells lay down a new basement membrane and release additional growth factors (e.g., PDGF) to recruit supporting cells for vessel stabilization. PDGFR: PDGF receptor; VEGFR: VEGF receptor. Cristofanilli M, Charnsangavej C, Hortobagyi GN. Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discov . 2002;1:415-426.
Molecular mechanisms leading to angiogenesis include disruption of von Hippel-Lindau (VHL) gene function and disruption of the mammalian target of rapamycin (mTOR) signal transduction pathway. 1-3 1. Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333. 2. Seeliger H, Guba M, Kleespies A, Jauch KW, Bruns CJ. Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev . 2007;26:611-621. 3. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents . Nat Rev Drug Discov . 2006;5:671-688.
Researchers have come to appreciate the role of the VHL gene in RCC, which in turn has led to a better understanding of the pathogenesis of RCC. VHL is a tumor suppressor gene located on chromosome 3p25. Several lines of evidence point to the importance of VHL in RCC pathology. Studies show that loss of heterozygosity of the VHL gene locus is detected in approximately 85%-95% of informative cases of clear-cell RCC. 1,2 Other studies show that VHL genetic abnormalities are present in 60%-90% of all patients with sporadic RCC. 3,4 In these studies, VHL was mutated in roughly 50%-70% of individuals, whereas it was silenced by hypermethylation in 5%-20%. Inactivation of VHL is thought to be a very early event in clear-cell tumorigenesis. 1. Shuin T, Kondo K, Torigoe S, et al. Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res . 1994;54:2852-2855. 2. Brauch H, Weirich G, Brieger J, et al. VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. Cancer Res . 2000;60:1942-1948. 3. Yao M, Yoshida M, Kishida T, et al. VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst . 2002;94:1569-1575. 4. Banks RE, Tirukonda P, Taylor C, et al. Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Res . 2006;66:2000-2011.
The VHL gene encodes a tumor suppressor protein that binds to several other proteins (elongin B, elongin C, Cul2, Rbx1, NEDD8) to form a multiprotein complex (VEC) that targets various proteins for destruction including hypoxia inducible factor 1 (HIF-1 ), a transcription factor that controls genes that allow cells to grow and survive in hypoxic conditions. Under normoxic conditions, HIF-1 is hydroxylated at specific amino acid resides, which allows the VHL complex to bind and ubiquitinate HIF-1 , thus targeting the protein for degradation by the proteasome. As a consequence, VHL controls hypoxia-inducible genes involved in angiogenesis, glycolysis, erythropoiesis, pH, cell adhesion, and extracellular membrane assembly. Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333.
Loss of VHL function, either through mutation or silencing (ie, hypermethylation), is functionally equivalent to hypoxic conditions. That is, VHL is unable to bind to HIF-1 to target the protein for destruction. As a consequence, HIF-1 accumulates and binds to its abundantly expressed partner, HIF-1 , in the cell nucleus to then induce gene transcription. Proteins upregulated by transcriptionally active HIF-1 /HIF-1 include VEGF, PDGF, transforming growth factor- (TGF- ), the glucose transporter protein GLUT-1, and carbonic anhydrase IX, among others. The effects of mutant VHL and HIF-1 on angiogenic factors such as VEGF and PDGF are thought to account for the high degree of vascularization seen in RCC tumors. Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333.
Upregulation of VEGF, PDGF, and EGFR by HIF-1 leads to the activation of several molecular pathways that contribute to cellular proliferation, cell survival, cell migration, and angiogenesis. 1,2 Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333. Vignot S, Faivre S, Aguiire D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol . 2005;16:525-537. [after fade] The most important of these pathways for growth stimulation, and the ones that have undergone the most intensive therapeutic investigation, include the Raf/MEK/ERK pathway and the PI3K/AKT pathway. 1,2 Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333. Vignot S, Faivre S, Aguiire D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol . 2005;16:525-537.
Downstream of PI3K and AKT lies mTOR, a central modulator that relays angiogenesis and nutrient-uptake signals to downstream proteins controlling transcription and translation. The mTOR pathway contributes to angiogenesis in 2 distinct ways: it mediates endothelial proliferation through VEGF signaling, and it activates activates angiogenic growth factors through increased production of the HIF-1 transcription factor. 1-3 Expression of the PTEN tumor suppressor gene, which is an upstream regulator of mTOR, has been shown to be downregulated and/or inactivated in RCC. 4,5 Seeliger H, Guba M, Kleespies A, Jauch KW, Bruns CJ. Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev . 2007;26:611-621. Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol . 2002;22:7004-7014. Mita MM, Mita A, Rowinsky EK. The molecular target of rapamycin (mTOR) as a the rapeutic target against cancer. Cancer Biol Ther . 2003;2:S169-S177. Yu Y, Sato JD. MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. J Cell Physiol . 1999;178:235-246. Brenner W, Färber G, Herget T, Lehr HA, Hengstler JG, Thüroff JW. Loss of tumor suppressor protein PTEN during renal carcinogenesis. Int J Cancer . 2002;99:53-57.
Knowledge of biologic basis of renal oncogenesis has facilitated the transition from a nonspecific immune approach using cytokines (ie, IL-2, IFN- ) to a molecular approach that targets the specific pathways involved in RCC pathology. Some of these agents have been FDA approved for the treatment of advanced RCC, whereas others are still considered investigational for this indication. 1 1. Stadler WM. Targeted agents for the treatment of advanced renal cell carcinoma. Cancer . 2005;104:2323-2333.
There are 4 targeted agents available for the treatment of advanced RCC. These agents are the first new drugs to be approved for RCC in almost 2 decades. Three of these agents target the VEGF pathway, whereas 1 targets the mTOR pathway. All of these agents significantly prolong the time to disease progression in comparison with either placebo or IFN-a. 1-5 As such, these agents represent the new standard of care for metastatic disease. ORR: overall response rate; PBO: placebo; TTP: time to progression. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet . 2007;370:2103-2111. 2. Rini BI, Halabi S, Rosenberg JE, et al. CALGB 90206: a phase III trial of bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in metastatic renal cell carcinoma. Program and abstracts of the 2008 American Society of Clinical Oncology Genitourinary Cancers Symposium; February 14-16, 2008; San Francisco, CA. Abstract 350. 3. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med . 2007;356:115-124. 4. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med . 2007;356:125-134. 5. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med . 2007;356:2271-2281.
