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The Rapidly Changing Landscape in RCC Therapy: What Future Research May Hold

Bradley Carthon, MD, PhD
Published: Wednesday, Oct 24, 2018

Bradley Carthon, MD, PhD

Bradley Carthon, MD, PhD

Assistant Professor
Department of Hematology and Medical Oncology
Emory University School of Medicine
Approximately 43,000 cases of kidney cancer in men and 23,000 cases in women will occur in the United States in 2018.1 Almost 90% of those cases will be renal cell carcinoma (RCC), generally affecting individuals between the ages of 50 and 70.1,2 There are varying histologies that make up RCC, with clear cell histology being the most common, accounting for 70% of all cases.2 No singular cause of kidney cancer, including RCC, is known.2 However, certain risk factors have been identified, including obesity, smoking, environmental exposures and family history or genetics.2

RCC can mutate quickly, and one-third of diagnosed patients present with metastatic disease.3,4 This is due to the fact that the majority of patients are identified incidentally while undergoing workup for another issue, as the “classic” triad of symptoms—including palpable flank mass, pain and hematuria—are often absent, especially in early kidney cancer.5 These and other signs and symptoms—such as loss of appetite, fatigue and unexplained weight loss—are often attributable to other benign causes and may not trigger an immediate checkup.2

Because presentation with metastatic disease is relatively common, long-term survival outcomes for patients with advanced RCC have been poor, with 5-year survival rates of 11.7% for patients with stage IV disease.3,6 These poor outcomes have prompted intensive clinical research aimed at developing novel therapeutic options addressing unmet needs of these patients.

While there have been important advances in research around metastatic RCC, work still remains. Recent median overall survival for metastatic RCC is still less than approximately 3.5 years, even in the best prognostic groups, and survival in those patients with poor risk factors is worse, at about 7.8 months in a recent study.7 According to criteria established by the International Metastatic Renal Cell Carcinoma Database Consortium, the majority of patients fall into either the intermediate- or poor-risk category, highlighting the continued urgency to develop new approaches for this disease.8

Current Research Focused on Advanced Disease

Given the unmet needs for patients with metastatic RCC, much of the research on treatment has been for this specific population. As such, molecularly targeted systemic therapies for advanced RCC have today often supplanted previously used therapies that are no longer supported by guidelines.9,10 The current research landscape may be roughly divided into 3 broad categories based on therapeutic targets: antiangiogenic agents, related molecular pathways such as the mTOR pathway, and immunotherapies—including cytokine therapy.9

Antiangiogenic agents make up the majority of metastatic RCC treatment options. Early studies of these agents utilized monoclonal antibodies against the VEGF molecule and small molecule inhibitors of the VEGF receptor.11,12 More recently, multiple oral receptor tyrosine kinase inhibitors (TKIs) with varying affinity for the VEGF receptor and other receptors have been developed.13

Another important therapeutic target, mTOR, forms complexes with other proteins that regulate various processes such as cellular growth, enhanced activity of the cell cycle, and deceased apoptosis.14 This pathway feeds back into the biologically important process of angiogenesis, inhibition of which may result in antitumor activity.14 While these agents have primarily been studied as monotherapies, there has also been recent investigation into the combination of mTOR-based agents and VEGFR inhibitors.4,14

Immunotherapy in RCC has been a therapeutic option for decades, as RCC has been well-established as an immunogenic cancer.15,16 Strategies include exploring how to activate the immune system directly and understand the processes by which cancer cells evade the immune system, which may in turn inform methods for inhibiting the suppression mechanisms of tumors.17-21 It is important to note that immunotherapy may also result in the attack of healthy cells along with cancerous cells.22

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Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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