Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 8/1/2020
Patients with recurrent renal cell cancer have cancer that has progressed with treatment or returned after being previously treated. Renal cell cancers may recur 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.
In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Treatments that may be available through clinical trials are discussed in the section titled “Strategies to Improve Treatment.”
Systemic Therapy for Renal Cell Cancer
Systemic therapy is any treatment directed at destroying cancer cells throughout the body. Advanced renal cell cancers that cannot be effectively treated with surgery can only be treated with systemic therapy.
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® (sunitinib) (1)
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.
Immunotherapy Immunotherapy Superior to TKI in Clear Cell RCC With Altered DDR Genes
Patients with metastatic clear cell RCC and a loss of function in DNA damage repair (DDR) genes have better survival outcomes when treated with immunotherapy versus tyrosine kinase inhibitor (TKI) therapy. ATM and CHEK2 were the most frequently altered genes. (12)
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. (2) Additionally, a Phase III trial has demonstrated that Sutent is superior to interferon-alfa. (3)
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®. (4)
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). (5) A later analysis of these data also suggested that Nexavar significantly improved overall survival.B ased on the results of this study, Nexavar was FDA-approved for use in renal cell cancer. (6)
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.7 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.
Liquid Biopsy Detects Disease Progression Much Earlier Than Imaging
What if a simple blood test could quickly determine when chemotherapy was ineffective and prevent its unnecessary use?
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. (8)
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.(9)
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.10
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).
To learn more about bone metastases and bone health, go to Bone Complications and Cancer
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.(11)
- 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
- 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.
- 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.
- 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 radomised, 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.
- Ged Y, Chaim J, Knezevic A, et al. Alterations in DNA damage repair (DDR) genes and outcomes to systemic therapy in 225 immune-oncology (IO) versus tyrosine kinase inhibitor (TKI) treated metastatic clear cell renal cell carcinoma (mccRCC) patients (pts). Presented at: the 2019 Genitourinary Cancers Symposium; February 14-16, 2019; San Francisco, CA. Abstract 551.