Treatment of Stage IV Renal Cell Cancer
Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)
Patients with Stage IV renal cell cancer 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.
Renal cell cancers are 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, targeted therapy, 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 therapies offer better outcomes.
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 renal cell cancer.1,2
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 renal cell cancer have distant metastases, surgery is typically followed with additional systemic treatment. Surgery is considered a local therapy because it treats cancer in a specific area but does not treat cancer that has spread to other locations in the body. Systemic (whole-body) treatments, such as targeted therapy and immunotherapy, can treat cancer that has spread throughout the body.
Some patients can 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 these cases 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
For individuals with stage IV renal cell cancer systemic therapy is administered after local treatment with surgery in order to decrease the chance of cancer recurrence. Despite undergoing surgery patients already have small amounts of cancer that have spread away from the kidney and were not removed during surgery. Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Systemic therapies commonly used in the treatment of renal cell cancer include the following:
Checkpoint inhibitors are a precision cancer immunotherapy that has clearly improved the treatment of cancer.
A comparative clinical study evaluating the checkpoint inhibitor Opdivo (nivolumab) plus Yervoy (ipilimumab) in patients with previously untreated advanced or metastatic renal cell carcinoma has been demonstrated to improve overall survival (OS) compared to Sutent®4
Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting 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, allowing 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.
Checkpoint inhibitors for the treatment of cancer
- Keytruda® (pembrolizumab)
- Opdivo (nivolumab)
- Imfinzi (durvalumab)
- Tecentriq® (atezolizumab)
Precision Cancer Medicines: A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Several precision cancer medicines are available for use in the management of renal cell cancer.
Sutent® (sunitinib): Sutent is an oral multitargeted tyrosine kinase inhibitor that targets proteins responsible for stimulating cancer cell growth. Two Phase II clinical trials have shown that approximately 40% of patients with recurrent renal cell cancer respond to treatment with Sutent, and approximately one-quarter of patients experienced stable disease for three months after treatment.5 Additionally, a Phase III trial has demonstrated that Sutent is superior to interferon-alfa.6
Afinitor® (everolimus). Afinitor is an oral targeted therapy that works by inhibiting a protein known as the mammalian target of rapamycin (mTOR). The mTOR protein plays an important role in the growth, division, and metabolism of cancer cells.
In a Phase II clinical trial, roughly 70% of patients with metastatic renal cell cancer experienced either a reduction in detectable cancer or stable disease following treatment with Afinitor®.7
Nexavar® (sorafenib): A Phase III clinical trial compared Nexavar to placebo in more than 900 patients with previously treated, advanced renal cell cancer. Treatment with Nexavar significantly improved progression-free survival (survival without a worsening of the cancer).8 A later analysis of these data also suggested that Nexavar significantly improved overall survival.9 Based on the results of this study, Nexavar was FDA-approved for use in renal cell cancer.
Torisel® (temsirolimus): The clinical trial that prompted FDA approval of Torisel included 626 patients with metastatic renal cell cancer who had a poor prognosis and had not received prior therapy.10 Patients were treated with either Torisel, interferon alfa, or a combination of Torisel plus interferon alfa (combination group).
- Patients treated with Torisel had longer survival by nearly 3.6 months and significantly longer progression-free survival than patients treated with interferon alone.
- Patients in the combination group did not experience a significant improvement in survival compared with patients treated with interferon alone.
- Fewer patients suffered from severe side effects in the group treated with Torisel than in the group treated with interferon.
Avastin® (bevacizumab): Avastin is a targeted therapy that blocks a protein known as VEGF. VEGF plays a key role in the development of new blood vessels. By blocking VEGF, Avastin deprives the cancer of nutrients and oxygen and inhibits its growth. For patients with metastatic kidney cancer, treatment with a combination of Avastin and interferon alfa results in a longer time to cancer progression than treatment with interferon alpha alone.11
Votrient (pazopanib): Votrient is a targeted oral medication known as an angiogenesis inhibitor. The drug may help slow or prevent the growth of new blood vessels, which deprives the cancer of the oxygen and nutrients it needs to grow. The approval of Votrient for advanced kidney carcinoma was prompted in part by a Phase III clinical trial showed that the drug delayed cancer progression.12
Immunotherapy: Immunotherapy works by stimulating the immune system to fight the cancer. Checkpoint inhibitors are relatively precise immunotherapy. Proleukin® (interleukin-2) and alfa interferon work in a more general manner to stimulate the bodies immune system.
Proleukin® (interleukin-2): Prior to the FDA-approval of newer precision cancer medicines, Proleukin was the standard of care for patients with advanced renal cell cancer. It is typically administered in high doses as an inpatient treatment and has historically been associated with severe side effects. The safety of high-dose Proleukin has significantly improved over the past decade.
Unfortunately, long-term results of clinical trials indicate that only approximately 15% of patients with advanced renal cell carcinoma have an anticancer response when treated with high-dose Proleukin.13
Interferon: Interferon is naturally produced in the body and stimulates the immune system. Interferon alfa is a compound produced in a laboratory that mimics the action of natural interferon and has been shown to stimulate the immune system to recognize and destroy some types of cancer cells.
Treatment of renal cell carcinoma with interferon appears to produce anticancer responses in less than 15% of patients with advanced renal cell cancer. Because side effects can be severe and it has not been shown to improve survival, the use of interferon alone in the treatment of renal cell carcinoma remains controversial.
Chemotherapy for Metastatic Renal Cell Cancer: Chemotherapy is any treatment involving the use of drugs to kill cancer cells. Cancer chemotherapy may consist of single drugs or combinations of drugs and can be administered through a vein or delivered orally in the form of a pill. Renal cell cancers have historically been resistant to treatment with chemotherapy; 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).
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 further 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.14
1 Flanigan RC, Salmon SE, Blumenstein BA et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. New England Journal of Medicine. 2001;345:1655-9.
2 Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomized trial. Lancet. 2001;966-70.
3 Friedel G, Hurtgen M, Penzenstadler M et al. Resection of pulmonary metastases from renal cell carcinoma. Anticancer Research. 1999;19(2C):1593-1596.
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 #18.
6 Motzer RJ, Hutson TE, Tomczak P et al. Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa (IFN-?) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mrcc). Presented at the 2006 ASCO Annual Meeting. Abstract #LBA3.
7 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.
8 Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal cell cancer. New EnglandJournal of Medicine. 2007; 356:125-34.
9 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.
10 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.
11 Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a radomised, double-blind phase III trial. Lancet. 2007;370:2103-11.
12 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.
13 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.
14 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.