Medication Summary
The goals of pharmacotherapy in renal cell carcinoma are to induce remission, reduce morbidity, and prevent complications. Selected patients with metastatic disease respond to immunotherapy, but many patients with advanced renal cell disease can be offered only palliative therapy.
Options for chemotherapy and endocrine-based approaches are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care. Objective response rates with chemotherapy, either single-agent or combination, are usually lower than 15%. Therefore, various biologic therapies have been evaluated. Targeted therapies that primarily block angiogenesis or cell growth pathways are commonly used for metastatic renal carcinoma.
Renal cell carcinoma is an immunogenic tumor, and spontaneous regressions have been documented. Many immune modulators have been tried, including the following:
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Interferon (IFN)
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Interleukin (IL)-2 (aldesleukin [Proleukin])
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Bacillus Calmette-Guérin (BCG) vaccination
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Lymphokine-activated killer (LAK) cells plus IL-2
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Tumor-infiltrating lymphocytes
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Nonmyeloablative allogeneic peripheral blood stem-cell transplantation
More recently, immune checkpoint inhibitors have been developed and approved for use in metastatic renal carcinoma. Results with these agents and other molecular-targeted therapies continue to emerge, and these agents are being approved for use.
Antineoplastic Agents
Class Summary
Few options are available for the systemic therapy of renal cell carcinoma (RCC), and no hormonal or chemotherapeutic regimen is accepted as a standard of care to treat this disease. Objective response rates, either for single or combination chemotherapy, are usually lower than 15%. Multikinase inhibitors induce objective responses in up to 40% of patients, but they are not known to cure patients with metastatic disease.
Aldesleukin (Proleukin)
Aldesleukin is an interleukin (IL)–2 product that is also known as a T-cell growth factor and activator of T cells and natural killer cells. It has been approved for the treatment of adults with metastatic renal cell carcinoma. This agent affects tumor growth by activating lymphoid cells in vivo, without affecting tumor proliferation directly.
Caution must be exercised in patients with preexisting cardiac, pulmonary, central nervous system (CNS), hepatic, or renal impairment. The major toxic effect of high-dose IL-2 is a sepsislike syndrome, which includes a progressive decrease in systemic vascular resistance and an associated decrease in intravascular volume due to capillary leak.
Vinblastine
Vinblastine is a vinca alkaloid with cytotoxic effects via mitotic arrest. This agent binds to a specific site on tubulin, preventing polymerization of tubulin dimers and inhibiting microtubule formation. Using the intrathecal route of administration may result in death.
Gemcitabine (Gemzar)
Gemcitabine is a cytidine analogue. After intracellular metabolism to active nucleotide, this agent inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA.
5-Fluorouracil
5-fluorouracil (5-FU) is a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and interferes with RNA synthesis and function. This agent has cell-cycle specificity with activity in S phase. 5-FU metabolites can incorporate into DNA and RNA, resulting in changes in DNA synthesis and RNA processing that impair cell turnover.
Paclitaxel
Paclitaxel has a mechanism of action that involves tubulin polymerization and microtubule stabilization, which, in turn, inhibits mitosis and may result in breakage of chromosomes.
Carboplatin
Carboplatin is an analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to action of these drugs in the G1 and S phase. It has the same efficacy as cisplatin but with a better toxicity profile.
Ifosfamide (Ifex)
Ifosfamide inhibits DNA and protein synthesis and, thus, cell-proliferation, by causing DNA cross-linking and denaturation of the double helix.
Doxorubicin
Doxorubicin is a cytotoxic anthracycline antibiotic that blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to the sugar-phosphate backbone of DNA, which causes DNA polymerase inhibition. It binds to nucleic acids, presumably by specific intercalation of the anthracycline nucleus with the DNA double helix. Doxorubicin is also a powerful iron chelator. The iron-doxorubicin complex induces the production of free radicals that can destroy DNA and cancer cells.
Floxuridine
Floxuridine is an antineoplastic antimetabolite that is most active during the S phase of the cell cycle. Floxuridine is catabolized to 5-fluorouracil when administered. Floxuridine inhibits DNA and RNA synthesis.
Interferon alfa-2a (Roferon A) and 2b (Intron A)
Interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. These agents have a direct antiproliferative effect on renal tumor cells, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules.
Caution should be exercised when administering interferons in patients with brain metastases, severe hepatic or renal insufficiency, seizure disorders, multiple sclerosis, or a compromised CNS.
PD-1/PD-L1 Inhibitors
Nivolumab (Opdivo)
Human immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response. Nivolumab monotherapy is indicated for patients with advanced RCC who have received prior antiangiogenic therapy (eg, VEGF inhibitors). It is also indicated in combination with ipilimumab for patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma. Nivolumab in combination with cabozantinib is indicated for first-line treatment of advanced RCC.
Pembrolizumab (Keytruda)
Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks interaction between PD-1 and its ligands, PD-L1 and PD-L2. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells. It is indicated as first-line treatment of advanced RCC in combination with axitinib.
Avelumab (Bavencio)
Anti-PD-L1 IgG1 monoclonal antibody. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen-presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. It is indicated in combination with axitinib for first-line treatment of advanced RCC.
Tyrosine kinase inhibitors and VEGF inhibitors
Sorafenib (Nexavar)
Sorafenib is indicated for advanced renal cell carcinoma. This agent was the first oral multikinase inhibitor that targeted serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Sorafenib targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation. These kinases included RAF kinase, vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-beta, stem cell factor receptor (KIT), and Fmslike tyrosine kinase-3 (FLT-3).
Axitinib (Inlyta)
Axitinib inhibits receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. It is indicated for treatment of advanced renal cell carcinoma after failure of 1 prior systemic therapy. Also, it is indicated in combination with pembrolizumab or avelumab for advanced cell carcinoma.
Sunitinib (Sutent)
Sunitinib is a multikinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. This agent inhibits PDGFRs (ie, PDGFR-alpha, PDGFR-beta), VEGFRs (ie, VEGFR1, VEGFR2, VEGFR3), KIT, FLT3, colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET).
Pazopanib (Votrient)
Pazopanib is a multityrosine kinase inhibitor indicated for advanced renal cell carcinoma. This agent selectively inhibits VEGFR-1, -2 and -3, c-kit, and PDGFR, which may result in inhibition of angiogenesis in tumors in which these receptors are upregulated. [58]
Lenvatinib (Lenvima)
Tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors for VEGFR-1, -2, -3, FGFR -1, -2, -3, and -4, PDGFR-alpha, KIT and RET pathways. The combination of everolimus and lenvatinib shows increased ant-angiogenesis properties. The combination is indicated for advanced renal cell carcinoma in patients who have received prior antiangiogenic therapy. It is indicated for advanced RCC in combination with everolimus following 1 prior antiangiogenic therapy.
Cabozantinib (Cabometyx)
Tyrosine kinase inhibitor that targets RET, MET, VEGFR-1, -2, and -3, KIT, TrkB, FLT-3, AXL, and TIE-2 pathways. It is indicated for advanced RCC. Also, it is indicated in combination with nivolumab, for first-line treatment of advanced RCC.
Bevacizumab (Avastin, Mvasi)
Bevacizumab is a recombinant, humanized monoclonal antibody that inhibits angiogenesis by targeting and inhibiting VEGF. Bevacizumab is indicated for the treatment of metastatic kidney cancer in combination with interferon alfa. Mvasi has been FDA-approved as a biosimilar to Avastin but not as an interchangeable product.
mTOr Kinase Inhibitor
Temsirolimus (Torisel)
Temsirolimus is a water-soluble ester of sirolimus that binds with high affinity to immunophilin FKBP (FK506 binding protein) and is indicated for advanced renal cell carcinoma. This complex inhibits mammalian target of rapamycin (mTOR) kinase, a key protein in cells that regulates gene translation responsible for cell cycle regulation. mTOR also reduces cell growth factors (eg, vascular endothelial growth factor [VEGF]) involved in new blood vessel development.
Everolimus (Afinitor)
Everolimus is a rapamycin-derivative kinase inhibitor that is indicated for advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. This agent reduces cell proliferation and angiogenesis by inhibition of mTOR pathway.
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Gross image of a bivalved kidney showing renal cell carcinoma in the upper half. The periphery of the carcinoma is yellow (due to high lipid content) with a central gelatinous area of necrosis.
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H and E, high power of a clear cell renal cell carcinoma. The tumor cells have abundant pale "clear" cytoplasm.
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H and E, low power of a papillary renal cell carcinoma. There are "finger-like" projections of fibrovascular stroma lined by malignant tumor cells that lack the abundant clear cytoplasm seen in a clear cell carcinoma.
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H and E, high power of a chromophobe RCC composed of cells with clear, reticular cytoplasm and some with eosinophilic cytoplasm. The cell borders are often more distinct in this carcinoma than others and the nuclei are often smaller and darker.
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H and E, high power of a collecting duct carcinoma composed of tubules lined by malignant cells in a background stroma that is fibrotic.
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Typical renal cell carcinoma. CT scan obtained before contrast enhancement has an attenuation measurement of 33.9 HU.
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