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Stage IV-Metastatic Renal Cancer

Patients with stage IV renal cell cancer (RCC) have cancer that has spread to distant sites in the body, invaded directly into local structures, or has spread to more than one lymph node. Stage IV disease is also known as metastatic cancer.

Advanced RCC is typically treated with both local and systemic therapy. Local therapy consists of surgery to remove the entire affected kidney and any surrounding cancer. Systemic therapy is directed at destroying cancer cells throughout the body and may include chemotherapy, precision cancer medicines, or immunotherapy. Renal cell cancers have historically been resistant to treatment with chemotherapy, and only 10–15% of patients experience an anticancer response to currently available single chemotherapy drugs. Newer targeted precision cancer medicines offer better outcomes.1,2,3,6

Surgery for Metastatic Renal Cell Cancer

The surgery for stage IV renal cell cancer is called a radical nephrectomy and involves removing the entire affected kidney, the attached adrenal gland, and any adjacent fat and involved lymph nodes or major blood vessels. Results from clinical trials have shown that radical nephrectomy appears to improve survival of patients with metastatic RCC.1,2,3

For patients with stage IV disease whose cancer has spread locally, but not to distant sites in the body, radical nephrectomy may be curative. However, because most patients with stage IV RCC have distant metastases, surgery is typically followed with additional systemic treatment. Systemic (whole-body) treatments are necessary to treat cancer that has spread throughout the body.

Some patients can also experience long-term cancer-free survival after surgical resection of metastatic cancers. Results of a clinical trial indicate that renal cell cancer that has spread to the lungs can be removed with surgery. Among patients treated with surgery for lung metastases but no evidence of cancer elsewhere in the body, including the kidney, nearly 40% survived five years or more. Patients with only a single site of cancer in the lung experienced the best outcomes; nearly 50% survived five years or more compared with 19% of patients who had more than one site of cancer removed.3

An alternative to surgery: It is frequently not possible to perform a radical nephrectomy in older or debilitated patients. In this case a procedure called arterial embolization is sometimes used to provide relief from pain or bleeding. During arterial embolization small pieces of a special gelatin sponge or other material are injected through a catheter to clog the main renal blood vessel. This procedure shrinks the cancer by depriving it of the oxygen-carrying blood that it needs to survive and grow. Arterial embolization may also be used prior to surgery to make the procedure easier.

Systemic Therapy for Stage IV Renal Cell Cancer

Systemic therapy is any treatment directed at destroying cancer cells throughout the body and is the cornerstone of treatment for metastatic and recurrent cancer. Systemic therapies used for the treatment of RCC include chemotherapy, immunotherapy, and/or precision cancer medicines.4,5,6 The current standard of care combines checkpoint inhibitor immunotherapy with the precision cancer medicine Inlyta® (axitinib).2,34

Inlyta is a small-molecule tyrosine kinase inhibitor that works by blocking certain proteins that play a role in cancer growth. The developers of the checkpoint inhibitor immunotherapy drugs Keytruda and Bavencio both elected to combine their medication with Inlyta in order to determine their effectiveness in the treatment of advanced RCC.

About Checkpoint inhibitors

Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system to fight cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses and allow cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells. There are several FDA approved checkpoint inhibitor medications.

Bavencio® (avelumab)

  • Keytruda® (pembrolizumab)
  • Opdivo (nivolumab)
  • Imfinzi (durvalumab)
  • Tecentriq® (atezolizumab)

Clinical trials have shown that combination of the PD-1 checkpoint inhibitor drugs Keytruda or Bavencio with Inlyta improves overall survival and delays cancer progression for patients with clear-cell metastatic renal cell carcinoma and produces superior outcomes, especially for individuals who are PD-L1+. The novel drug combination trial results were published in the New England Journal of Medicine and led to a US Food and Drug Administration (FDA) approval for the first-line treatment of patients with advanced RCC in May 2019.2,3

Another comparative clinical study evaluated the checkpoint inhibitor Opdivo (nivolumab) combined with Yervoy (ipilimumab) in patients with previously untreated advanced or metastatic renal cell carcinoma and the combination demonstrated improved overall survival.4

Chemotherapy for Metastatic Renal Cell Cancer: Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Renal cell cancers have historically been resistant to treatment with chemotherapy and only 10–15% of patients experience an anticancer response to currently available single chemotherapy drugs.

Managing Bone Complications

Renal cell cancer may spread to the bone. Bone metastases may cause pain, bone loss, an increased risk of fractures, and a life-threatening condition characterized by a high level of calcium in the blood, called hypercalcemia.

Drugs that may be used to reduce the risk of complications from bone metastases include bisphosphonates and Xgeva® (denosumab). Bisphosphonates, such as Zometa® (zoledronic acid), work by inhibiting bone resorption, or breakdown. Xgeva targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone).

Recurrent Renal Cell Carcinoma

Renal cell cancers may return locally, in the area of the kidney, or in other parts of the body such as the lungs or bones. Recurrent renal cell cancers are typically treated with systemic therapy and some may also benefit from local therapy consisting of surgery to remove areas of metastatic disease.

Standard treatment is with the checkpoint inhibitor Inlyta combination if not already used, otherwise combinations of other precision cancer medicines, immunotherapy, or participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. There are several medications approved for the treatment of advanced or recurrent RCC.


1 American Cancer Society. What is kidney cancer? Available from: Accessed July 2018.




5 George D, Motzer R, Rini B, et al. Sunitinib malate (SU11248) shows antitumor activity in patients with metastatic renal cell carcinoma: updated results from Phase II trials. Proceedings from the 2005 annual Chemotherapy Foundation Symposium. New York, NY. Abstract

6 Amato RJ, Jac J, Giessinger S et al. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer [early online publication]. March 20, 2009.

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