**Author details**

160mg once daily on a 3 weeks on/1 week off schedule. The primary endpoint was overall response rate. Preliminary efficacy data of the 33 patients evaluable for response show a 27%

Currently, we have the fortunate problem of having several agents demonstrating effica‐ cy in the first- and second-line setting, with a number of other small molecule inhibitors that target VEGFR tyrosine kinase being evaluated in mRCC consistently showing activi‐ ty. With similar mechanisms of action, clinical responses have been observed, including in patients that have previously received TKI therapy. Part of the challenge in moving forward is the lack of understanding of the biologic underpinnings of resistance to the currently approved agents and uniform clinical definitions of what truly constitutes treat‐

Studies combining targeted therapies are being performed with the known caveat that combinations are associated with high financial cost and risk of increased toxicity due to additive and overlapping side effect profiles. Rational combinations of active agents continue to be evaluated. Currently, combinations of targeted therapy remain experimental and they

Targeted agents are also being studied in the adjuvant setting for patients with resected highrisk RCC. The Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma (ASSURE) intergroup trial randomizes high-risk nephrectomized patients to 1 year of sor‐ afenib, sunitinib or placebo (estimated enrolment: 1332, primary endpoint: disease-free survival (DFS)) (NCT00326898). Other trials such as the phase III sunitinib versus placebo study for the treatment of patients at high risk of recurrent RCC (S-TRAC: estimated en‐ rolment 236, primary endpoint: DFS) (NCT00375674) and the sorafenib versus placebo tri‐ al in patients with resected intermediate or high-risk RCC (SORCE: estimated enrolment 1656, primary endpoint: DFS) (NCT00492258) will further help elucidate the effect of

One of the next directions in the therapy of advanced RCC involves the combination of several targeted agents to better inhibit a single pathway at several different levels or inhibition at the same level of several pathways mediating different effects. As combinations of targeted agents undergo investigation, it will be critical for these combinations to demonstrate clinical benefit above and beyond those of sequential monotherapy with the same agents, in order to justify the added toxicity and risk. Thus, prospective data in this regard are critical, and some data

partial response (PR) and a 42% stable disease (SD) rate [27].

should only be employed in the context of a clinical trial.

these agents in the adjuvant setting.

**13. Combination therapy**

have recently emerged.

**12. Sequence of targeted therapy**

ment resistance.

152 Renal Tumor

V. Michalaki, M. Balafouta, D. Voros and C. Gennatas

Oncology Unit Areteion Hospital Univesity of Athens, Greece

## **References**

[1] Campbell, S. C, & Lane, B. R. (2012). Malignant renal tumors. In A. Wein, L. Kavoussi, A. Novick, A. Partin, & C. Peters (Eds.), Campbell-Walsh urology (10th ed., Philadel‐ phia: Elsevier Saunders., 1413-1474.

[14] Motzer, R. J, Hutson, T. E, Tomczak, P, Michaelson, M. D, Bukowski, R. M, Rixe, O, et al. (2007b). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J

Current Perspectives in Metastatic Renal Cell Carcinoma Treatment: The Role of Targeted Therapies

http://dx.doi.org/10.5772/54856

155

[15] Motzer, R. J, Michaelson, M. D, Rosenberg, J, Bukowski, R. M, Curti, B. D, George, D. J, et al. (2007a). Sunitinib efficacy against advanced renal cell carcinoma. J Urol , 178,

[16] Witteles, R. M, Telli, M. L, Fisher, G. A, & Srinivas, S. (2008). Cardiotoxicity associated

[17] Heng, D. Y, Chi, K. N, Murray, N, Jin, T, Garcia, J. A, Bukowski, R. M, et al. (2009). A population-based study evaluating the impact of sunitinib on overall survival in the

[18] Ahmad, T, & Eisen, T. (2004). Kinase inhibition with BAY in renal cell carcinoma. Clin

[19] Escudier, B, Eisen, T, Stadler, W. M, Szczylik, C, Oudard, S, Siebels, M, et al. (2007a). Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med , 356, 125-134.

[20] Escudier, B, Szczylik, C, Hutson, T. E, Demkow, T, Staehler, M, Rolland, F, et al. (2009a). Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol , 27, 1280-1289.

[21] Atkins, M. B, Hidalgo, M, Stadler, W. M, Logan, T. F, Dutcher, J. P, Hudes, G. R, et al. (2004). Randomized phase II study of multiple dose levels of CCI-779, a novel mam‐ malian target of rapamycin kinase inhibitor, in patients with advanced refractory renal

[22] Hudes, G, Carducci, M, Tomczak, P, Dutcher, J, Figlin, R, Kapoor, A, et al. (2007). Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med ,

[23] Kay, A, Motzer, R, Figlin, R, Escudier, B, Oudard, S, Porta, C, et al. (2009). Updated data from a phase III randomized trial of everolimus (RAD001) versus PBO in meta‐ static renal cell carcinoma (mRCC). Genitourinary Cancers Symposium, February

[24] Rini, B. I, Wilding, G, Hudes, G, Stadler, W. M, Kim, S, Tarazi, J. C, et al. (2007). Axitinib (AG-013736; AG) in patients (pts) with metastatic renal cell cancer (RCC) refractory to

[25] Rixe, O, Bukowski, R. M, Michaelson, M. D, Wilding, G, Hudes, G. R, Bolte, O, et al. (2007). Axitinib treatment in patients with cytokine-refractory metastatic renal-cell

[26] Sternberg, C. N, Szczylik, C, Lee, E, Salman, P. V, Mardiak, J, Davis, I. D, et al. (2009). A randomized, double-blind phase III study of pazopanib in treatment-naive and

treatment of patients with metastatic renal cell cancer. Cancer , 115, 776-783.

with the cancer therapeutic agent sunitinib malate. J Clin Oncol 26: 9597.

Med , 356, 115-124.

Cancer Res 10: 6388S-92S., 43-9006.

cell carcinoma. J Clin Oncol , 22, 909-918.

356, 2271-2281.

Orlando., 26-28.

sorafenib. J Clin Oncol 25: 5032.

cancer: a phase II study. Lancet Oncol , 8, 975-984.

1883-1887.


[14] Motzer, R. J, Hutson, T. E, Tomczak, P, Michaelson, M. D, Bukowski, R. M, Rixe, O, et al. (2007b). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med , 356, 115-124.

**References**

154 Renal Tumor

Biol. (2012).

4536-4541.

18(Suppl 10): x, 3-10.

phia: Elsevier Saunders., 1413-1474.

human cancer. Oncogene , 24, 7455-7464.

esis therapy. J Nucleic Acids. (2012).

carcinoma. J Clin Oncol , 26, 127-131.

[1] Campbell, S. C, & Lane, B. R. (2012). Malignant renal tumors. In A. Wein, L. Kavoussi, A. Novick, A. Partin, & C. Peters (Eds.), Campbell-Walsh urology (10th ed., Philadel‐

[2] Barrisford, G. W, Singer, E. A, Rosner, I. L, Linehan, W. M, & Bratslavsky, G. Familial renal cancer: molecular genetics and surgical management.Int J Surg Oncol. (2011).

[3] Rini, B. I, & Small, E. J. (2005). Biology and clinical development of vascular endothelial growth factortargeted therapy in renal cell carcinoma. J Clin Oncol , 23, 1028-1043.

[4] Altomare, D. A, & Testa, J. R. (2005). Perturbations of the AKT signaling pathway in

[5] Hudson, C. C, Liu, M, Chiang, G. G, Otterness, D. M, Loomis, D. C, Kaper, F, et al. (2002). Regulation of hypoxia-inducible factor 1alpha expression and function by the

[6] Shen, C. Kaelin WG Jr. The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer

[7] Medici, D, & Olsen, B. R. Rapamycin Inhibits Proliferation of Hemangioma Endothelial Cells by Reducing HIF-Dependent Expression of VEGF. PLoS One. (2012). e42913.., 1.

[8] Pal, S. K, Williams, S, Josephson, D. Y, Carmichael, C, Vogelzang, N. J, & Quinn, D. I. Novel therapies for metastatic renal cell carcinoma: efforts to expand beyond the VEGF/

[9] Hilmi, C, Guyot, M, & Pagès, G. VEGF spliced variants: possible role of anti-angiogen‐

[10] Bukowski, R. M, Kabbinavar, F. F, Figlin, R. A, Flaherty, K, Srinivas, S, Vaishampayan, U, et al. (2007). Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol , 25,

[11] Choueiri, T. K, Plantade, A, Elson, P, Negrier, S, Ravaud, A, Oudard, S, et al. (2008). Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell

[12] Christensen, J. G. (2007). A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. Ann Oncol

[13] Mendel, D. B, Laird, A. D, Xin, X, Louie, S. G, Christensen, J. G, Li, G, et al. (2003). In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res , 9, 327-337.

mTOR signaling paradigm. Mol Cancer Ther. (2012). Mar;, 11(3), 526-37.

mammalian target of rapamycin. Mol Cell Biol , 22, 7004-7014.


cytokine-pretreated patients with advanced renal cell carcinoma (RCC). J Clin Oncol 27: 5021.

**Chapter 10**

**New Systemic Treatment Approaches for Metastatic**

Kidney cancer comprises 2-3% of all cancers according to Cancer Research UK statistics. (http:// info.cancerresearchuk.org). Renal Cell Carcinomas (RCC) is the most common subtype (around 90%) with clear-cell variant constituting up to 75% of all RCCs. Non clear-cell variant are less common and consist of papillary (Type I and II; 10-15%), chromophobe (4%) and collecting duct (including the rare medullary variant; <1%). [1, 2] At initial diagnosis, one third of patients have evidence of distant metastases, and amongst patients who undergo curative nephrectomy, a third will have a recurrence within 5 years. Historically, treatment options have been limited in metastatic RCC, as cytotoxic chemotherapy is not effective in this disease and immunotherapy is of modest benefit. [1] The treatment outlook for metastatic RCC has changed in the past decade, with the introduction of new therapeutic agents which target

The discovery of von Hippel–Lindau (VHL) / hypoxia-inducible factor (HIF) oxygen-sensing pathway and its role in the pathogenesis of RCC (clear-cell as well as some of the non-clearcell variant), has led to a new approach in the systemic therapy for RCC. [1, 3] Tumour suppressor gene VHL encodes the VHL protein (pVHL), which interacts with hypoxiainducible factor (HIF) to regulate cellular response to oxygen deprivation. HIF is a gene

> © 2013 Tan et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 Tan et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

distribution, and reproduction in any medium, provided the original work is properly cited.

**Renal Cell Carcinoma**

Michail Charakidis

**1. Introduction**

http://dx.doi.org/10.5772/55280

Thean Hsiang Tan, Sina Vatandoust and

Additional information is available at the end of the chapter

molecular pathways involved in tumour angiogenesis.

**2. Molecular pathogenesis**

**2.1. Clear- cell variants renal cell carcinoma**

[27] Eisen, T, Joensuu, H, Nathan, P, Harper, P, Wojtukiewicz, M, Nicholson, S, et al. (2009). Phase II study of BAY a multikinase inhibitor, in previously untreated patients with metastatic or unresectable renal cell cancer. J Clin Oncol 27: 5033., 73-4506.
