Renal Cell Carcinoma Medication
- Author: Kush Sachdeva, MD; Chief Editor: Jules E Harris, MD, FACP, FRCPC more...
The goals of pharmacotherapy 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.
Renal cell carcinoma is an immunogenic tumor, and spontaneous regressions have been documented. Many immune modulators have been tried, including the following:
Interleukin (IL)-2 (aldesleukin [Proleukin])
Bacillus Calmette-Guérin (BCG) vaccination
Lymphokine-activated killer (LAK) cells plus IL-2
Nonmyeloablative allogeneic peripheral blood stem-cell transplantation
More recently, targeted therapy agents have emerged. These have yielded encouraging results.
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 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 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 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-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 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 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 inhibits DNA and protein synthesis and, thus, cell-proliferation, by causing DNA cross-linking and denaturation of the double helix.
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 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.
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).
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).
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.
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.
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.
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.
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.
Bevacizumab is a recombinant, humanized monoclonal antibody that inhibits angiogenesis by targeting and inhibiting VEGF. Bevacizumab is FDA approved for the treatment of metastatic kidney cancer in combination with interferon alfa.
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.
Nivolumab is a monoclonal antibody to programmed cell death–1 protein (PD-1). PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. 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. Nivolumab is indicated for patients with advanced RCC who have received prior anti-angiogenic therapy (eg, VEGF inhibitors).
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 renal cell carcinoma in patients who have received prior antiangiogenic therapy.
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|Cell Type||Features||Growth Pattern||Cell of Origin||Cytogenetics|
|Clear cell||Most common||Acinar or sarcomatoid||Proximal tubule||3p-|
|Chromophilic||Bilateral and multifocal||Papillary or sarcomatoid||Proximal tubule||+7, +17, -Y|
|Chromophobic||Indolent course||Solid, tubular, or sarcomatoid||Cortical collecting duct||Hypodiploid|
|Oncocytic||Rarely metastasize||Tumor nests||Cortical collecting duct||Undetermined|
|Collecting duct||Very aggressive||Papillary or sarcomatoid||Medullary collecting duct||Undetermined|