Sorafenib and Sunitinib: Novel Targeted Therapies for Renal Cell Cancer
Sorafenib and Sunitinib: Novel Targeted Therapies for Renal Cell Cancer
Renal cell cancer (RCC) is a relatively uncommon malignancy, with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High-dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low-dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia-inducible factor and the Ras-Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first- and second-line therapy in patients with cytokine-refractory metastatic RCC who have clear-cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression-free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first- and second-line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand-foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.
In 2007, in the United States, 51,190 people are expected to be diagnosed with renal cell cancer (RCC), and 12,890 people are expected to die from it. Renal cell cancer is the seventh most common malignancy in men and the ninth most common in women. The disease is predominant in men (1.6:1): 31,590 cases are expected to be diagnosed in men and 19,600 in women in 2007. In addition, RCC is largely a disease of the elderly, with a median age at diagnosis of 65 years.
The 5-year survival rate for patients with localized disease is approximately 90%, drops to 60% in patients with locally advanced disease, and declines again to 20% in those with metastatic disease. Unfortunately, an estimated 30% of patients are diagnosed with advanced disease, and about half the patients who are treated for localized disease relapse with metastatic disease. Thus, developing effective therapy for advanced RCC may prolong survival and decrease mortality rates.
In the middle to late 1980s, cytokine-based therapy with interferon alfa or aldesleukin became the first major treatment advance for metastatic RCC. During the past 5 years, however, researchers have made excellent progress in understanding RCC biology, providing insight into the treatment of this malignancy. These advances have led to the development of a new class of drugs: multiple-kinase inhibitors. The United States Food and Drug Administration (FDA) recently approved two multiple-kinase inhibitors—sorafenib and sunitinib—for treatment of advanced RCC.
Renal cell cancer (RCC) is a relatively uncommon malignancy, with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High-dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low-dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia-inducible factor and the Ras-Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first- and second-line therapy in patients with cytokine-refractory metastatic RCC who have clear-cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression-free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first- and second-line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand-foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.
In 2007, in the United States, 51,190 people are expected to be diagnosed with renal cell cancer (RCC), and 12,890 people are expected to die from it. Renal cell cancer is the seventh most common malignancy in men and the ninth most common in women. The disease is predominant in men (1.6:1): 31,590 cases are expected to be diagnosed in men and 19,600 in women in 2007. In addition, RCC is largely a disease of the elderly, with a median age at diagnosis of 65 years.
The 5-year survival rate for patients with localized disease is approximately 90%, drops to 60% in patients with locally advanced disease, and declines again to 20% in those with metastatic disease. Unfortunately, an estimated 30% of patients are diagnosed with advanced disease, and about half the patients who are treated for localized disease relapse with metastatic disease. Thus, developing effective therapy for advanced RCC may prolong survival and decrease mortality rates.
In the middle to late 1980s, cytokine-based therapy with interferon alfa or aldesleukin became the first major treatment advance for metastatic RCC. During the past 5 years, however, researchers have made excellent progress in understanding RCC biology, providing insight into the treatment of this malignancy. These advances have led to the development of a new class of drugs: multiple-kinase inhibitors. The United States Food and Drug Administration (FDA) recently approved two multiple-kinase inhibitors—sorafenib and sunitinib—for treatment of advanced RCC.
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