Stages of Renal Cancer
Treatment of Stage I – III Renal Cancer
Overview
Stage I Renal Cancer: Patients with stage I renal cell cancer (RCC) have a primary cancer that is less than 7 centimeters in size (about 3 inches). The cancer is contained within the kidney and has not spread to lymph nodes or distant sites.
Patients with stage I renal cell cancer are curable with surgical removal of the cancer. Partial nephrectomy, which is removal of only the cancer and a small border of normal tissue, is the standard treatment for the smallest renal cancer (less than 4 centimeters in diameter). Depending on the size of the cancer and the function of the second kidney, some surgeons may recommend radical nephrectomy, or removal of the entire kidney. However, partial nephrectomy appears to be as effective as radical nephrectomy and preserves kidney function. Results of clinical trials have shown that 75-96% of patients with Stage I renal cancers are curable with surgery alone.1
Stage II Renal Cell Cancer: Patients with stage II renal cell cancer have a primary cancer that is larger than 7 centimeters (about 3 inches) in diameter. The cancer is limited to the kidney and has not spread to lymph nodes or distant sites.
Patients with stage II renal cell cancer are curable with surgical removal of the cancer. Radical nephrectomy, or removal of the entire affected kidney, is the standard treatment for cancers of this size. However, removal of only the cancer and a small border of normal tissue, a procedure known as a partial nephrectomy is being evaluated in the treatment of larger cancers that are surgically accessible. Results of clinical trials have shown that 63-95% of patients with stage II renal cancers are curable with surgery alone.2
Radical nephrectomy: Surgery for stage II renal cell cancer historically has involved removing the entire affected kidney and the attached adrenal gland, a procedure called a radical nephrectomy. Less invasive surgeries are being perfected and may be an option for many patients.
In some cases, the adrenal gland may not need to be removed. The adrenal glands are complex organs that work with the brain to produce and regulate important hormones, including adrenaline for coping with physical and emotional stress, corticosteroids for suppressing inflammation, and cortisol for controlling the body’s use of fats, proteins, and carbohydrates.
Researchers have reported that patients who underwent nephrectomy but did not have the adrenal gland removed survived as long as patients who underwent nephrectomy with removal of the adrenal gland and were not at any higher risk of postoperative complications.2
Stage III Renal Cell Cancer: Though stage III renal cell cancers vary in size, they share a defining feature of spread of the cancer to a single lymph node. The cancer may also have spread to nearby blood vessels—including the renal veins or vena cava—but has not spread to distant sites in the body.
Treatment for stage III renal cell cancer typically involves surgery to remove the affected kidney, affected lymph nodes, and any other cancer that may have spread near the kidney plus the attached adrenal gland and fatty tissue. This surgery is known as a radical nephrectomy. Results from clinical trials have shown that 38-70% of patients with stage III renal cell cancer are curable with surgery alone.1 However, patients with stage III disease have cancer that has spread outside the kidney, which places them at higher risk for cancer recurrence.
Partial nephrectomy (nephron-sparing surgery)
Removing only the cancer and some surrounding healthy tissue—a procedure called a partial nephrectomy—is now considered the standard of care for the treatment of small renal cancers. The benefits of this approach are shorter hospitalization and recovery time and, importantly, kidney function is preserved, which is particularly valuable for patients who already have poor function or only one kidney. Preserving the affected kidney is also valuable in the event that the cancer should recur in the opposite (contralateral) kidney.
The benefits and safety of this approach have been repeatedly demonstrated in the treatment of patients with Stage T1a renal cancer, which is defined a cancer that is less than 4 centimeters in diameter.2,3
Partial nephrectomy also appears to be a viable treatment option for patients with Stage T1b cancers (which are 4-7 centimeters in diameter) if an adequate amount of normal tissue surrounding the cancer can be removed.4 Patients with these slightly larger stage I cancers who are treated with partial nephrectomy have been shown to live as long and experience a similar cancer-free duration as patients treated with radical nephrectomy.5
However, longer follow up aimed at confirming these findings are ongoing. For those patients with stage T1b cancer that is more centrally located or those with multiple tumors, radical nephrectomy may be a better option.
Laparoscopic surgery
Laparoscopic surgery is a technique that is less extensive and invasive than traditional, open surgery. During a laparoscopic surgery for renal cancer, the surgeon makes small, one-centimeter incisions in the abdomen and side. The surgeon then inserts a very small tube that holds a video camera, which creates a live picture of the inside of the patient’s body. This picture is continually displayed on a television screen, so that surgeons can perform the entire surgery by watching the screen.
Both radical nephrectomy and partial nephrectomy may be conducted using laparoscopy. In the case of a radical nephrectomy, the incision is enlarged to allow passage of the kidney. A small bulk of tissue is removed with a partial nephrectomy and the incision can remain small.
Laparoscopic radical nephrectomy has emerged as an alternative to open surgery in the management of smaller (less than 8 centimeters in diameter), localized renal cancers. Patients treated with the laparoscopic approach do not appear to be at greater risk for cancer recurrence 5-10 years after treatment compared to patients treated open radical nephrectomy. The two approaches have also been shown to result in similar survival.6 However, patients who are candidates for laparoscopic radical nephrectomy would also do well with partial nephrectomy. The advantages of laparoscopic radical nephrectomy (shorter hospital stay and faster recovery) must be balanced with the advantage of partial nephrectomy, which is better long-term renal function.6,7,8,9,10,11,12
Laparoscopic partial nephrectomy appears to provide outcomes comparable to conventional open partial nephrectomy. Results of a clinical trial involving 100 patients with an average cancer size of 3.1 cm who underwent laparoscopic surgery showed that all patients survived three and one-half years or more after treatment without evidence of cancer recurrence.8 Laparoscopic partial nephrectomy is a specialized technique and should only be conducted by a surgeon who is experienced in this procedure.
Adjuvant therapy
The US Food and Drug Administration has approved one treatment for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy.
The approval of the medication Sutent (sunitinib malate) was based on a multi-center, clinical trial in which 615 patients with high risk RCC were treated with surgical nephrectomy and then received additional treatment either Sutent once daily, 4 weeks on treatment followed by 2 weeks off, or no additional therapy and directly compared. The average duration of survival without cancer recurrence for patients taking Sutent was 6.8 years compared with 5.6 years years for those receiving no additional treatment. Sutent is the first medication approved for use following surgery in high risk renal cell cancer.13
References
1 Lam JS, Shvarts O, Pantuck AJ. Changing concepts in the surgical management of renal cell carcinoma. European Urology. 2004; 45:692-705.
2 Joniau S, Vander Eeckt K, Van Poppel H. The indications for partial nephrectomy in the treatment of renal cell carcinoma. Nature Clinical Practice Urology. 2006;3(4):198-205.
3 Becker F, Siemer S, Humke U, et al. Elective nephron sparing surgery should become standard treatment for small unilateral renal cell carcinoma: Long-term survival data of 216 patients. European Urology. 2006;49(2):308-13.
4 Leibovich BC, Blute ML, Cheville JC, et al. Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy. Journal of Urology. 2004;171(3):1066-70.
5 Dash A, Vickers AJ, Schachter LR, et al. Comparison of outcomes in elective partial vs radical nephrectomy for clear cell renal cell carcinoma of 4-7 cm. British Journal of Urology International.2006;97(5):939-45.
6 Permpongkosol S, Chan DY, Link RE, et al. Long-term survival analysis after laparoscopic radical nephrectomy. Journal of Urology. 2005; 174:1222-1225.
7 Matin SF, Gill IS, Worley S, et al. Outcome of laparoscopic radical and open partial nephrectomy for the sporadic 4 cm. or less renal tumor with a normal contralateral kidney. Journal of Urology. 2002;168(4 Pt 1):1356-9.
8 Moinzadeh A, Gill IS, Finelli A, et al. Laparoscopic partial nephrectomy: 3-year followup. Journal of Urology. 2006;175(2):459-62.
9 Varkarakis IO, Allaf ME, Takeshi I, et al. Percutaneous radio frequency ablation of renal masses: results at a 2-year mean followup. Journal of Urology. 2005; 174:456-460.
10 Schwartz BF, Rewcastle JC, Powell T, et al. Cryoablation of small peripheral renal masses: a retrospective analysis. Urology. 2006;68(1):14-8.
11 Lam JS, Shvarts O, Pantuck AJ. Changing concepts in the surgical management of renal cell carcinoma. European Urology. 2004; 45:692-705.
12 Siemer S, Lehmann J, Kamradt J, et al. Adrenal metastases in 1635 patients with renal cell carcinoma: outcome and indication for adrenalectomy. Journal of Urology. 2004;171(6 Pt 1):2155-9.
13 https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm585686.htm
Stage IV-Metastatic Renal Cancer
Overview
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).2,3,4
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.
References
1 American Cancer Society. What is kidney cancer? Available from: https://www.cancer.org/cancer/kidney-cancer/about.html. 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.