97 Renal Cell Carcinoma: Treatment of Advanced Kidney Cancer
Surgical resection is a good curative option for localized renal cell carcinoma (RCC), but the cancer often recurs or presents as metastatic cancer due to the silent nature of the disease. Once metastatic, the disease is generally not curable, but there are many palliative options. Therapeutic options for metastatic clear cell RCC include immunotherapy, molecularly targeted agents, surgery, and radiation.
THERAPEUTIC OPTIONS AND APPROACH
For newly diagnosed or newly metastatic RCC patients, we need to keep in mind the histology of the tumor as well as risks that stratify them. More than 60% of patients with RCC have clear cell histology. Patients are deemed poor risk if they have three or more of the following criteria (CHALKS):
C = Calcium greater than 10 (corrected calcium)
H = Hemoglobin less than normal
A = Absence of kidney (or interval of <1 year between diagnosis and systemic therapy)
L = LDH greater than 1.5 × normal
K = Karnofsky performance status (KPS) less than 80%
S = Sites of metastatic disease greater than two
Immunotherapy is an important option for the management of patients with advanced clear cell RCC, both as initial therapy or as secondary therapy after molecularly targeted therapy. High-dose bolus IL-2 can activate an immune response against RCC that results in prolonged tumor regression in a minority of patients. Although treatment with high-dose IL-2 is associated with severe toxicity and requires specialized centers, it is also the only therapy that can provide long-term remission in certain patients, even in the absence of additional therapy. Therefore, it is an important option for carefully selected patients. Good candidates for high-dose IL-2 have excellent performance status, clear cell histology, and minimal metastatic disease burden.
Other immunotherapy options that are upcoming are PDL1 and PD1 inhibitors. Nivolumab has shown prolonged overall survival (OS) compared to everolimus as a second-line therapy and is now being employed as a second line therapy once patients fail targeted therapy. Interferon alpha (IFN-α) is another option that was previously used but has now been largely replaced by newer immunotherapy and targeted options due to partial and shorter responses.
VEGF Inhibitors: These agents work by targeting the vascular endothelial growth factor (VEGF) pathway. They are either small molecule tyrosine kinase inhibitors (TKIs) like sunitinib, pazopanib, cabozantinib, axitinib, or sorafenib, or a monoclonal antibody such as bevacizumab. TKIs prolong OS compared with IFN-α for the initial management of advanced RCC and are also active in the treatment of patients with disease progression after cytokine therapy. Therefore, they are the preferred first-line treatment in the majority of patients except when the patient is a candidate for IL-2 or when the patient’s disease falls in the poor risk category. In the absence of prior immunotherapy, generally treatment is started off with sunitinib, pazopanib, or a combination of bevacizumab and IFN-α. Sunitinib and pazopanib are generally preferred and have similar efficacy (Table 15.1).
99If prior immunotherapy has been used as first-line therapy, TKIs can be employed as second-line. Axitinib is the slightly preferred option as it is the most selective of the VEGF TKIs, but pazopanib or sunitinib can also be used.
Once a patient’s cancer has progressed on a first-line TKI, immunotherapy (nivolumab) can be used, but other TKIs such as cabozantinib can also be employed. The previously mentioned TKIs also remain an option, as does sorafenib. While a number of agents are available, data is limited in comparing them to each other, especially in the second-line and subsequent settings (Table 15.2).
mTOR inhibitors: The mTOR pathway is downstream of the phosphoinositide 3-kinase and Akt pathway. Current mTOR inhibitors include temsirolimus and everolimus. The principal utility for temsirolimus in RCC is as first-line therapy for poor risk RCC or for those with mutations in the PI3K pathway. Everolimus may be used in patients whose disease is refractory to initial treatment with VEGF receptor TKIs and/or those patients whose tumors have mutations in the PI3K pathway. However, it cannot replace temsirolimus for poor risk disease.