Current Therapeutic Approaches to Renal Cell Carcinoma

From the Department of Medicine, Carole and Ray Neag Comprehensive Cancer Center, UConn Health, Farmington, CT (Dr. Namakydoust and Dr. Clement) and the UConn School of Pharmacy, Storrs, CT (Dr. Holle).

Abstract

• Objective: To review therapeutic options for the treatment of renal cell carcinoma (RCC).
• Methods: Review of the literature in the context of a clinical case.
• Results: RCC accounts for 90% of all renal tumors. For RCC patients with nondistant metastases, preferred treatment is curative-intent radical nephrectomy or partial nephrectomy; oncologic outcomes for the 2 procedures are similar. For patients who are deemed not to be surgical candidates, ablative techniques such as cryoablation and radiofrequency ablation may be considered. Systemic therapy for metastatic RCC is based on the histologic type of the tumor. Clear-cell is by far the predominant histologic type in RCC. First-line treatment options for patients with metastatic clear-cell RCC include biologic agents such as high-dose interleukin-2 immune therapy, as well as targeted therapies including tyrosine kinase inhibitors (TKIs) and anti-VEGF antibodies. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is recommended as first-line therapy in patients with poor prognosis. Second-line therapies in this setting include TKIs and nivolumab (PD-1 inhibitor). If TKIs were used as first-line therapy, mTOR inhibitors can be used in the second line. In addition, after initial cytokine therapy, TKIs, temsirolimus, and the anti-VEGF antibody bevacizumab are other treatment options. Best supportive care should always be provided along with initial and subsequent therapies.
• Conclusion: Multiple treatment options are now available for patients with metastatic or unresectable RCC. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.

Renal cell carcinoma (RCC) is the most common malignancy arising in the kidney, comprising 90% of all renal tumors [1]. Approximately 55,000 new RCC cases are diagnosed each year [1]. Patients with RCC are often asymptomatic, and most cases are discovered as incidental findings on abdominal imaging performed during evaluation of nonrenal complaints. Limited-stage RCC that is found early can be cured sur-gically, with estimated 5-year survival rates approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20% [2]. Advanced RCC is resistant to conventional chemotherapy and radiotherapy, and outcomes for patients with metastatic or unresectable RCC remain poor. However, the recent development of new therapeutic modalities that target tumor molecular pathways has expanded the treatment options for these patients and changed the management of RCC.

Epidemiology and Classification

Median age at diagnosis in the United States is 64 years. Men have a higher incidence of RCC than women, with the highest incidence seen in American Indian and Alaska Native men (30.1 per 100,000 population). Genetic syndromes account for 2% to 4% of all RCCs [2]. Risk factors for RCC include smoking, hypertension, obesity, and acquired cystic kidney disease that is associated with end-stage renal failure [3]. Longer duration of tobacco use is associated with a more aggressive course.

The 2004 World Health Organization classification of renal tumors summarizes the previous classification systems (including the Heidelberg and Mainz classification systems) to describe different categories of RCC based on histologic and molecular genetics characteristics [2]. Using the WHO classification criteria, RCC comprises 90% of all renal tumors, with clear cell being the most common type (80%) [2]. Other types of renal tumors include papillary, chromophobe, oncocytoma, and collecting-duct or Bellini duct tumors. Approximately 3% to 5% of tumors are unclassified. Oncocytomas are generally considered benign, and chromophobe tumors typically have an indolent course and rarely metastasize. Sarcomatoid differentiation can be seen in any histologic type and is associated with a worse prognosis.

Familial Syndromes

Several genetic syndromes have been identified by studying families with inherited RCC. Among these, von Hippel-Lindau (VHL) gene mutation is the most commonly found inherited genetic defect. Table 1 summarizes the incidence of gene mutations and the corresponding histologic appearance of the most common sporadic and hereditary RCCs [4].

VHL disease is an autosomal dominant familial syndrome. Patients with this mutation are at higher risk for developing RCC (clear cell histology), retinal angiomas, pheochromocytomas, as well as hemangioblastomas of the central nervous system (CNS) [4]. Of all the genetic mutations seen in RCC, the somatic mutation in the VHL tumor-suppressor gene is by far the most common [5]. VHL targets hypoxia–inducible factor-1 alpha (HIF-α) for ubiquitination and subsequent degradation, which has been shown to suppress the growth of clear-cell RCC in mouse models [6–8]. HIF expression under hypoxic conditions leads to activation of a number of genes important in blood vessel development, cell proliferation, and glucose metabolism, including vascular endothelial growth factor (VEGF), erythropoietin, platelet-derived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), and glucose transporter-1 (GLUT-1). Mutation in the VHL gene prevents degradation of the HIF-α protein, thereby leading to increased expression of these downstream proteins, including MET and Axl. The upregulation of these angiogenic factors is thought to be the underlying process for increased vascularity of CNS hemangioblastomas and clear-cell renal tumors in VHL disease [4–8].

Other less common genetic syndromes seen in hereditary RCC include hereditary papillary RCC, hereditary leiomyomatosis, and Birt-Hogg-Dubé (BHD) syndrome [9]. In hereditary papillary RCC, the MET gene is mutated. BHD syndrome is a rare, autosomal dominant syndrome characterized by hair follicle hamartomas of the face and neck. About 15% of patients have multiple renal tumors, the majority of which are of the chromophobe or mixed chromophobe-oncocytoma histology. The BHD gene encodes the protein folliculin, which is thought to be a tumor-suppressor gene.