Novel targeted therapies have extended survival for patients with renal cell cancer, and provide the practicing oncologist with a new array of treatment options. Although clinical data about the effectiveness of targeted therapies for both treatment-naive and metastatic renal cell cancer patients is increasingly robust, questions remain about how to choose among them, according to several speakers at an educational session of the 2010 Genitourinary (GU) Cancers Symposium.¹ The toxicities associated with targeted therapies are generally manageable, but the use of these agents requires proactive monitoring, researchers at the symposium commented. The 2010 Genitourinary Cancers Symposium was cosponsored by ASCO, the American Society for Therapeutic Radiology and Oncology, and the Society of Urologic Oncology.

Research Limitations

Targeted therapies, including vascular endothelial growth factor (VEGF) inhibitors like sorafenib (Nexavar) and mammalian target of rapamycin (mTOR) inhibitors such as temsirolimus (Torisel), have improved survival rates among metastatic renal cell cancer patients-extending average lifespan to 2 years, according to Gary R. Hudes, MD, of the Fox Chase Cancer Center. But questions about how to compare these targeted agents and how to use them in practice have still not been entirely resolved, he noted. Very few clinical trials have compared targeted therapies head-to-head, although a number of comparative phase III trials-as well as those that are studying targeted therapies in combination-are ongoing, Dr. Hudes said. He also noted that a study published in the Journal of Clinical Oncology in 2009 found that choice of initial therapy did not impact overall survival in renal cell cancer patients.² "We have an increasing number of options especially for favorable- and intermediate-risk patients, but optimal therapy is not yet well defined," Dr. Hudes said. "We need comparative efficacy and tolerability trials, as well as those that study these agents in combination and in the adjuvant setting," he said.

Treatment of refractory or resistant metastatic renal cell cancer, however, continues to be challenging for clinicians, according to Elisabeth I. Heath, MD, of the Karmanos Cancer Institute at Wayne State University in Detroit. A growing number of FDA-approved targeted therapies are available in the metastatic setting, and it can be difficult to judge which to use for patients who have failed previous therapies. VEGF inhibitors for metastatic renal cell cancer include sorafenib, sunitinib (Sutent), bevacizumab (Avastin), and pazopanib (Votrient).

Of these agents, sorafenib has the most robust clinical data supporting its use in metastatic renal cell carcinoma after failed cytokine therapy, Dr. Heath said. In the phase III TARGET investigation (Treatment Approaches in Renal Cancer Global Evaluation Trial), sorafenib therapy resulted in a significantly improved progression-free survival, and in an expanded access study of patients with advanced renal cell cancer, sorafenib resulted in prolonged stable disease, Dr. Heath said.³

Among the mTOR inhibitors, minimal evidence supports the use of temsirolimus for metastatic renal cell cancer, but significant data also exist regarding the use of everolimus (Afinitor) in post-targeted therapy failure as well as post-cytokine therapy failure, according to Dr. Heath. One phase III trial of everolimus compared with placebo found few objective responses but a significant improvement in progression-free survival.⁴

Ongoing trials are also testing the effectiveness of combination therapies, and research has led to new agents that target novel pathways involved in renal cell cancer. "The list of emerging targets is tremendous, and not all are related to mTOR or VEGF," Dr. Heath said. When deciding upon treatment choices for patients with metastatic disease, clinical data should be considered important-but so should the mechanisms of biologic resistance, patient convenience, and insurance questions, she added.

Monitoring and Managing Toxicities

Although targeted therapies offer the promise of improved efficacy for renal cell cancer patients, they come with mild to moderate toxicities, according to Thomas E. Hutson, DO, PharmD, of the Baylor Sammons Cancer Center and Texas Oncology in Dallas. Because these agents are not curative and must be administered chronically, management of toxicities is an important issue. Some of the toxicities associated with targeted agents include cardiovascular disorders such as hypertension, skin conditions, and changes in glucose and cholesterol metabolism, Dr. Hutson said. Cardiovascular toxicity appears to be linked to VEGF inhibition, and the development and severity of hypertension is thought to reflect the extent of target inhibition, Dr. Hutson said. As many as 50% of patients on VEGF and mTOR inhibitors also experience skin changes such as hand-foot syndrome, skin rashes, and mucositis/functional stomatitis, he added. Alterations in glucose and cholesterol metabolism are unique and expected toxicities of the mTOR inhibitors.

Management of toxicities requires regular monitoring and early intervention, Dr. Hutson said. Antihypertensive therapy and, in severe cases, temporary suspension of therapy may be required to control hypertension. Skin toxicities can be managed with supportive and palliative interventions, as well as education of the patient and caregiver regarding early and prompt recognition of skin changes. Oncologists should also monitor patients carefully for metabolic toxicities, and these side effects may require diet modification, initiation of insulin, oral agents for glycemic control, or lipid-lowering agents. "Optimal treatment with targeted agents requires proactive intervention and management of side effects to avoid dose reductions or interruptions, and to make sure that patients get the full benefit of these therapies," Dr. Hutson said. ■

References

1. Genitourinary Cancers Symposium. General Session VIII: Renal Cancer-Metastatic Renal Cell Carcinoma. Presented March 7, 2010.

2. Heng DY, Xie W, Regan MM, et al: Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. J Clin Oncol 27:5794-5799, 2009.

3. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcionoma. N Engl J Med 356:125-134, 2007.

4. Motzer RJ, Escudier B, Oudard S, et al: Efficacy of everolimus in advanced renal cell carcinoma: A double-blind randomized placebo-controlled phase III trial. Lancet 372:449-456, 2008.