by Dr. C.H. Weaver M.D. Medical Editor updated 11/2021
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 may be treated with local and systemic therapy and selected patients may undergo active surveillance. Local therapy may consist of surgery to remove the affected kidney and any surrounding cancer. Systemic therapy is directed at destroying cancer cells throughout the body and may include precision cancer medicines, immunotherapy or chemotherapy. Renal cell cancers were historically resistant to treatment with chemotherapy - only 10–15% of patients experienced an anticancer response. Newer targeted precision cancer medicines and immunotherapy prolong survival and offer the possibility of cure for certain patients.1,2,5,6
Selected "good risk" patients without any of the following risk factors may forego initial treatment in favor of active surveillance. Individuals with 1 or 2 risks factors are considered to be intermediate risk and those 3 or more are high risk for cancer recurrence.
- Diminished performance status
- Time from diagnosis to treatment less than 1 year.
- Higher blood calcium levels.
- Elevated platelet and/or white blood count.
Surgery for Metastatic Renal Cell Cancer
The role of surgery in the management of stage IV RCC may consist of removal of isolated areas of metastases and radical nephrectomy. A radical nephrectomy involves removing the entire affected kidney, the attached adrenal gland, and any adjacent fat and involved lymph nodes or major blood vessels. Results from older clinical trials demonstrated that radical nephrectomy improved survival of patients with metastatic RCC, however more recent studies cast some doubt on the role of surgery. Some research suggests that newer precision immunotherapy treatments are so effective that surgery may not be necessary. (1-3) Patients considering nephrectomy should discuss its role with an experienced team of doctors that treat RCC.
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.4-15 The current standard of care uses immunotherapy combinations or combines checkpoint inhibitor immunotherapy with the precision cancer medicine Inlyta® (axitinib).4-6
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 2019.5,6
The US Food and Drug Administration (FDA) has approved the checkpoint inhibitor Opdivo (nivolumab) combined with Yervoy as first-line, treatment for patients with advanced kidney cancer. Long term survival analyses of the CheckMate 214 clinical trial evaluating Opdivo plus (ipilimumab) immunotherapy in comparison to Sutent (sunitinib) in patients with advanced renal cell carcinoma was presented at the International Kidney Cancer Symposium in November 2021. In this trial 1096 patients with clear cell were randomly treated with the immunotherapy combination and directly compared to individuals treated with Sutent. Patients were more likely to respond to the combination of Odivo and Yervoy and live longer without cancer progression. Almost 50% of patients treated with immunotherapy survived 5 years and 30% had no evidence of cancer progression compared to only 14% of those treated with Sutent.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).
To learn more about bone metastases and bone health, go to Bone Complications and Cancer
Recurrent Renal Cell Carcinoma
Renal cell cancers typically develop resistance to treatment. Resistant cancer may return locally in the area of the kidney, or in other parts of the body such as the lungs or bones. Its important to understand that not all sites of recurrence are the same. Different cancer causing mutations may lead to resistance in different locations of the body and some of these resistant cancers can be effectively treated by surgical removal while areas continue to respond to systemic treatment.
Standard treatment for recurrent cancer is with the checkpoint inhibitor combinations 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.
Doctors can perform NGS - biomarker testing on a biopsy sample to help determine whether surgery may be beneficial and to identify cancer driving mutations that could be treated with newer precision cancer medicines available through clinical trials.
- Systemic therapy is cornerstone of treatment with checkpoint inhibitor immunotherapy.
- TKI therapy is preferred if checkpoint inhibitor has already been used.
- NGS - biomarker testing to determine if isolated metastases can be surgically removed and to determine clinical trial participation.
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Areas of active investigation aimed at improving the treatment of renal cell cancer include the following:
New Precision Cancer Medicines: Researchers continue to explore new targeted therapies that may improve outcomes among people with advanced kidney cancer.
Combination Therapy: Combinations of immunotherapy, chemotherapy and precision cancer medicines, called regimens, may produce more anticancer responses and improve the outcomes of patients with advanced renal cell cancer than treatment with any single therapy. Combination therapy can take advantage of potential drug synergies and non-overlapping side effects to improve clinical benefit. Clinical trials are ongoing evaluating combinations to determine whether they can improve the outcome of patients compared with the use of any single drug.
Vaccines for Renal Cell Cancer: Vaccines are comprised of proteins that stimulate the immune system to destroy foreign substances in the body, such as bacteria. Vaccines are also being developed that stimulate the immune system to recognize cancer cells as harmful and destroy them. Cancer vaccines are typically made from proteins that are more abundantly present on cancer cells than normal cells. The patient’s own cancer cells are often used to make the vaccine, which is one reason that vaccines may be difficult to prepare. The patient’s cancer cells must be processed immediately following surgery. Therefore, patients and their surgeons must prepare in advance to ensure that the removed cancer cells can be handled properly for vaccine preparation.
A vaccine comprised of cells from the patient’s cancer has been shown to improve progression-free survival compared to surgery alone in the treatment of patients with renal cell cancer. Nearly three-quarters of the patients treated with the vaccine survived approximately six years or more compared with 59% of those treated with surgery alone. This research is ongoing. (15)
- American Cancer Society. What is kidney cancer? Available [here]. Accessed July 2018(https://www.cancer.org/cancer/kidney-cancer/about.html).
- Keytruda- Inlyta Treatment Combination Improves Outcomes in Renal Cell Caner
- CheckMate -214 Study Evaluating Opdivo in Combination with Yervoy Stopped Early for Demonstrating Overall Survival Benefit in Patients with Previously Untreated Advanced or Metastatic Renal Cell Carcinoma
- Keytruda- Inlyta Treatment Combination Improves Outcomes in Renal Cell Caner
- 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 #18.
- 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.
- Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal cell cancer. New EnglandJournal of Medicine. 2007; 356:125-34.
- Bukowski RM, Eisen T, Szczylik C et al. Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: survival and biomarker analysis. Presented at the 2007 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL. Abstract 5023.
- Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal cell carcinoma. New England Journal of Medicine. 2007; 356:2271-2281.
- Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103-11.
- Sternberg CN, Davis ID, Mardiak J et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. Journal of Clinical Oncology. 2010;28:1061-1068.
- Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. Journal of Clinical Oncology. 1995;13(3):688-696.
- Jocham D, Richter A, Hoffmann L, et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomized controlled trial. The Lancet. 2004; 363:594-599.