Renal cell cancer

INTRODUCTION — Renal cancer is a condition in which one or more cancerous tumors develop in one or both kidneys. Over time, the tumors grow in size and can invade surrounding tissues. In its more advanced stages, renal cancer can metastasize (spread throughout the body), causing tumors to develop in other organs.

Primary renal cancer refers to cancerous tumors that originate in the kidney. The kidneys can also develop metastatic or secondary tumors as a result of cancer spreading from some other part of the body. There are several types of primary renal cancer: Renal cell carcinomas (RCCs) comprise 80 to 85 percent of all renal cancers; they typically arise in the renal cortex (the outer layer of the kidney). Within the category of RCC, there are several subtypes: clear cell or conventional RCC is the most common (80 percent), chromophilic or papillary RCCs (15 percent), and chromophobic carcinomas (5 percent) account for the majority of the remainder. Collecting duct tumors account for <1 percent of RCC. A variant called sarcomatoid renal cancer, which can occur with any of the subtypes, is the most aggressive. Transitional cell carcinomas arise within a portion of the kidney called the renal pelvis, where the urine collects before being transported to the bladder for storage. These types of tumors are more closely related to bladder cancer than to renal cancers, and they are treated similarly. Wilms tumor, also called nephroblastoma, is another type of kidney tumor that is found most commonly in children.

Here we will focus on the symptoms, diagnosis, and treatment of primary renal cell carcinoma.

RISK FACTORS — Primary RCC most often develops after the age of 50. It is more common in men than in women, and in blacks as compared to white (non-Hispanic) people. In men, kidney cancer is the seventh most common cancer, and is the tenth most common cause of cancer-related death.

Although the specific cause of kidney cancer is unknown in the majority of cases, a number of factors can increase the risk for developing a primary RCC.

Cigarette smoking — Cigarette smoking doubles the risk for developing RCC, and it is a contributory factor in one-third of all cases.

Occupational exposure — Occupational exposure to substances such as cadmium, asbestos, and petroleum by-products increases the risk for RCC.

Obesity — Increased body weight appears to be associated with an increased risk for RCC in both men and women.

Acquired cystic disease of the kidney — Acquired cystic disease of the kidney develops in a large percentage of patients who are on chronic dialysis because of kidney failure. Approximately 30 percent of patients with acquired cystic disease will develop RCC.

Analgesic abuse — Prolonged use of analgesics containing aspirin and a compound called phenacetin (banned in the United States since 1987) can lead to kidney failure, and also places patients at increased risk for renal cancers. The majority of these are transitional cell cancers; the association of analgesic abuse with RCC remains controversial.

Genetic factors — Certain inherited disorders such as von Hippel-Lindau syndrome, Birt Hogg Dube syndrome, and tuberous sclerosis are associated with an increased risk for RCC. Heredity can also play a role in patients who do not have an easily traceable genetic disease. For example, patients who have a close relative who developed RCC before age 40, or who have developed primary cancer in both kidneys (ie, bilateral) or in multiple sites within the same kidney may have a hereditary component.

Periodic screening of urine or abdominal ultrasound may be recommended for patients with an inherited predisposition to RCC. This includes patients with von Hippel-Lindau syndrome, Birt Hogg Dube syndrome, or tuberous sclerosis, those who have been on dialysis for several years, and those with a strong family history of RCC.

SYMPTOMS — The classic presenting symptoms of RCC are hematuria (blood in the urine), flank pain (pain in the side at the level of the lower ribcage), and an abdominal mass. However, most cancers do not produce pain, and many patients with primary RCC experience no symptoms until the disease is advanced. An increasing percentage (up to 40 percent) of patients are diagnosed with RCC incidentally, based upon a radiologic procedure such as ultrasound or CT scan that was performed for other reasons.

Local tumor growth may produce other symptoms as nearby organs are affected. For example, invasion of the vena cava (a large vein near the kidney) can result in liver dysfunction or fluid collection in the abdomen or legs, and invasion of the left renal vein can produce left side scrotal swelling (varicocele).

The cancer can also spread, or metastasize, to other organs, causing additional symptoms. The most common sites of metastasis are the nearby lymph glands or nodes, lungs, bones, liver, brain, the nearby adrenal gland, and the opposite kidney. The symptoms of metastatic disease vary according to the organs that are affected, and can include cough, shortness of breath, or bone pain and fractures.

RCCs (renal cell cancers) sometimes produce excessive amounts of various hormones. Secretion of these substances by the tumor may disrupt body processes that are sensitive to these hormones. A range of laboratory abnormalities, such as an increase in the red blood cell count, and an increase in the levels of calcium in the blood, and associated symptoms, may result.

Patients with RCC may also develop systemic or body-wide symptoms that are common among patients who have cancer. These include loss of appetite, weight loss, intermittent fever, night sweats, and fatigue.

DIAGNOSIS — If a kidney cancer is suspected, an abdominal CT scan is usually performed to evaluate the extent of kidney involvement and determine whether the tumor has invaded surrounding tissues and organs. A tissue biopsy is required to confirm the diagnosis.

Other studies, including a CT scan of the chest, a bone scan, and an abdominal MRI may also be performed to assess for metastases or involvement of adjacent structures.

Tissue biopsy — In a biopsy procedure, a small portion of tissue is obtained by using a thin needle. The tissue (or cells) is then examined by the pathologist to determine if it contains cancer. Most patients with suspected RCC do not require a biopsy. If radiographic studies are judged to be highly suspicious for an isolated RCC, surgery to remove the entire tumor is usually performed in lieu of biopsy. In patients with suspected metastases, it may be sufficient to biopsy the metastatic areas rather than the primary renal tumor.

STAGING — Following the diagnostic work-up, the extent of the cancer is staged (described) based upon information about the primary kidney tumor (the tumor or "T" stage), the status of the lymph nodes in the area (the nodal or "N" stage), and the presence or absence of any metastases (the "M" stage) (show table 1). Different combinations of these T, N, and M classifications are grouped together (stage groupings) to form four different stages of disease, based upon similarities in outcome for each stage, I through IV (show table 2).

In broad terms, the stages of RCC are as follows:

Stage I — Patients with stage I RCC have a small (less than 7 cm) tumor that is limited to the kidney. They have no evidence of lymph node involvement or metastatic disease.

Stage II — Patients with stage II RCC have a larger (greater than 7 cm) tumor that is limited to the kidney. In addition, there is no evidence of lymph node involvement or metastatic disease.

Stage III — In patients with stage III disease, the tumor has invaded the adrenal gland (which sits atop each kidney), tissues surrounding the kidney, or major nearby veins, such as the vena cava. Stage III disease also includes patients with enlarged abdominal lymph nodes.

Stage IV — Patients with stage IV disease are those who have large tumors that extend into surrounding tissues, and/or metastasis to other distant locations.

Staging information is useful in determining treatment and prognosis. In general, patients with earlier stage disease have the most favorable prognosis or outcome.

SURGICAL TREATMENT — Treatment for RCC may include surgery, radiation therapy, or medications such as immunotherapy, chemotherapy, anti-angiogenic therapy, and a variety of experimental agents. The treatment plan is determined by the stage of the disease.

Potentially curative surgical treatment — Surgery that attempts to cure the cancer may be offered to patients with early RCC (stage I, II or III disease). When the cancer has not spread beyond the kidney, local surgery offers a reasonable chance for a cure. Several types of surgery may be considered. Potentially curative surgery usually consists of either a radical or partial (nephron-sparing) nephrectomy.

Radical nephrectomy — Radical nephrectomy is generally recommended for tumors larger than 4 cm. The procedure requires removal of the entire kidney through an incision in the abdomen or side. The remaining, normal kidney takes over the function of filtering the blood to remove toxins and excess water. The nearby adrenal gland and regional lymph nodes may also be removed in this procedure, and parts of adjacent organs that are involved with the cancer may also require resection.

Patients who have tumors smaller than 10 cm may be able to have a radical nephrectomy performed via several smaller incisions through a laparoscope (laparoscopic surgery). Although this is more technically demanding for the surgeon, studies suggest that the cancer-related outcome is similar to that of an open radical nephrectomy, while patient recovery is often much faster.

Partial nephrectomy — In a partial nephrectomy, the tumor and some of the surrounding kidney tissue are removed in order to remove the cancer while sparing some of the functional units of the kidney (the nephrons, hence the term nephron-sparing surgery). The option of partial nephrectomy is limited to patients with small tumors (less than 4 cm in size) that appear to be isolated to one kidney, and to patients with small bilateral tumors. It may also be performed in patients whose kidney function is impaired and might be further compromised by the removal of an entire kidney.

Cryoablation and radiofrequency ablation — Other nephron-sparing ways of treating RCC, include cryoablation (destroying the tumor by a freezing technique) and radiofrequency ablation (RFA, destroying the tumor by using radiofrequency heat energy). These procedures may be particularly useful if partial or radical nephrectomy are not an option due to a patient's underlying medical condition(s). Data regarding the long-term risks and benefits of RFA and cryoablation are not known, although short-term follow-up appears promising. Careful surveillance is required after either procedure due to the risk of recurrence or residual disease. Surveillance typically includes CT or MRI, although it is unclear how frequently this should be done.

Surgery in patients with advanced RCC — For patients who have more advanced disease, surgery is sometimes performed in conjunction with medical therapy (see "Medical therapy" below). For example, in some patients with advanced disease, the response to immunotherapy may be enhanced by surgical removal of the kidney tumor. This is sometimes referred to as debulking or cytoreductive surgery; the goal is to remove as much of the tumor as possible so that immunotherapy is more likely to slow or stop progression of the cancer.

Similarly, surgical removal of metastatic tumors (particularly those involving the lungs) may be beneficial for patients who have a limited number of metastatic sites and have controlled disease in the kidney. As many as one-quarter of these patients survive without a recurrence of their cancer for five years or longer, particularly those with a long interval between the original nephrectomy and the development of metastases.

MEDICAL THERAPY — RCC is often silent until it has reached an advanced stage, meaning that potentially curative surgery is not an option for many patients. Medical treatment may be recommended for patients who are diagnosed with advanced RCC and those whose cancer has recurred (grown or spread) after surgery.

Interleukin-2 immunotherapy — Immunotherapy is considered the standard form of medical treatment for advanced renal cancer. The immune system encompasses a complex set of mechanisms that help to fight and protect the body from harmful substances. These immune mechanisms are triggered when a foreign substance is detected by the body. Renal tumors may be recognized as foreign substances, which increases their sensitivity to therapies that activate the immune system.

Removal of the kidney (debulking) — Surgical debulking procedure is recommended for some patients before immunotherapy since this improves the chances of a positive response to immunotherapy.

Interleukin-2 — The most active immunotherapy drug used to treat RCC is interleukin-2 (IL-2). High dose IL-2 was previously the standard treatment for advanced RCC. However, it can cause serious, even toxic side effects, and some patients are not able to tolerate it. When completed, IL-2 produces tumor shrinkage in 15 to 20 percent of patients, with nearly half of the tumor responses being complete and many being long-lasting [1].

Patients who achieve either a complete response to IL-2 alone, or a partial response with later surgical resection of all remaining tumor, who remain free of disease recurrence for 30 months following treatment are unlikely to later relapse and may in fact be "cured".

Thus, high-dose IL-2 is considered by many to be the preferred treatment for patients with advanced RCC who are able to tolerate it. Efforts to identify the subset of patients who benefit from high dose IL-2 are ongoing, with the hope of restricting this intensive therapy to those most likely to benefit. In addition, the role of high dose IL-2 is being reassessed in light of the recent availability of anti-angiogenic agents (see "Anti-angiogenic therapy" below).

Side effects of IL-2 — High dose IL-2 can cause serious side effects, and patients must be treated in the hospital and closely monitored (often in the intensive care unit) during therapy. Due to the risk of serious side effects, patients who undergo IL-2 therapy should receive care from centers that are capable of providing close monitoring and can respond rapidly in case of complications during treatment.

Common side effects include flu-like symptoms (muscle and joint aches, low grade fever, chills), nausea, vomiting, diarrhea, low blood pressure, shortness of breath, confusion, skin rash, and a temporary drop in the platelet count. Additional medications or interventions can be used to minimize toxic effects and relieve unpleasant symptoms.

Alternate immunotherapy regimens — Due to the toxic effects of high-dose IL-2, multiple alternative dosing plans and combination therapy regimens with other immune-active agents (eg, interferon) have been studied for patients who would not be able to tolerate IL-2. Prior to the development of anti-angiogenic therapy, lower dose IL-2 or interferon were the only options for these patients.

Anti-angiogenic therapy — Angiogenesis is the development of new blood vessels, which is a critical step in the growth of tumors. Efforts to find treatments that target the process of angiogenesis have been successful; encouraging results have been seen with several agents that slow the growth of blood vessels developing in cancerous tumors.

Sorafenib and sunitinib are currently available for patients with advanced RCC. Neither produce long-term remission or cure; thus, the timing of these treatments relative to immunotherapy (such as high-dose IL-2) requires careful consideration. Clinical trials are ongoing to determine when and how these treatments should be used to optimize survival.

Sorafenib — Results of a trial comparing sorafenib (Nexavar®) to placebo showed that sorafenib prevented progression of RCC for a longer period of time [2]. Patients in this trial had advanced RCC and had failed prior therapy with IL-2. The placebo group had no progression for 12 weeks compared to 24 weeks in the sorafenib group. Over 70 percent of patients in the sorafenib group had some degree of tumor shrinkage.

Sorafenib is taken as two pills twice daily on an empty stomach. Common side effects include diarrhea, skin rashes, mild hand-foot skin reactions, elevated blood pressure, and changes in blood tests (phosphate and liver enzyme levels) and nerve sensation (neuropathy). Patients should be monitored closely by their healthcare provider during treatment.

Sunitinib — Similar to sorafenib, sunitinib (Sutent®) may be used for treatment of patients with advanced RCC. Early studies have shown that it is safe for most patients and can induce tumor shrinkage in the majority of patients. Clinical trials are ongoing to better define the role of this medication in the management of RCC.

Early trials with sunitinib showed that 40 percent of patients had a partial response with measurable tumor shrinkage. In a later trial, sunitinib was compared to interferon in patients who had previously received no treatment. A greater number of patients responded to sunitinib compared to interferon (31 versus 6 percent), and progression free survival (when there was no growth of the cancer) was prolonged with sunitinib compared to interferon (11 versus 5 months) [3]. Further research is needed to determine if overall survival will also be improved with sunitinib compared to interferon.

Side effects with sunitinib include fatigue, high blood pressure, nausea, diarrhea, sores of the mouth and gastrointestinal tract, thyroid problems, and changes in liver function testing. Sunitinib is typically taken as a pill once daily for four weeks, followed by a two week rest period.

Chemotherapy — Chemotherapy refers to drugs that kill cancer cells because they interfere with their ability to grow and reproduce, and is often used for treatment of cancer in other organ systems (eg, breast cancer). However, RCC is generally resistant to chemotherapy; however some RCC variants including collecting duct tumors and tumors with extensive sarcomatoid features may respond well to specific chemotherapy regimens.

Summary — High-dose bolus IL-2 is considered to be the preferred treatment for many patients with advanced RCC; some patients will achieve a prolonged, disease-free remission. However, not all patients are candidates for IL-2 due to the risk of serious side effects or various features of the tumor. Patients who are not candidates for high-dose IL-2 or who progress after receiving IL-2 are candidates for anti-angiogenic therapies, which can produce tumor shrinkage or delay disease progression in the majority of patients with RCC.

SYMPTOM MANAGEMENT — In addition to treating the primary disease, medical management of patients with advanced RCC focuses on relieving pain and other symptoms. Pain is often treated with analgesics. Blood clots can sometimes develop in the urinary tract and cause spasms. Spasms may be relieved by the administration of fluids and insertion of a stent that keeps the urinary tract open and allows clots to pass through.

Therapeutic embolization — Kidney cancers often cause bleeding since they contain a large blood supply. Embolization is a non-invasive procedure in which a gelatin-like substance is injected into selected blood vessels that supply the kidney cancer. The gelatin forms a barrier that blocks blood flow to the area perfused by the blood vessels.

Embolization may be done to lower the risk of hemorrhage (bleeding) during nephrectomy in patients with large tumors. It is also used to control symptoms, such as bleeding and pain, in patients who are not candidates for surgery or have metastases.

Radiation therapy — Tumors that metastasize to areas outside the kidney can cause pain. Radiation treatment can be used to relieve pain from metastatic tumors. At sites such as the brain and lungs, radiation therapy is used to reduce tumor size and manage some symptoms that occur as a consequence of metastatic tumor involvement.

CLINICAL TRIALS — Progress in treating renal cell cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/


WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Institute of Diabetes and Digestive and Kidney Diseases

(www.niddk.nih.gov)
National Cancer Institute

(www.nci.nih.gov/)
American Cancer Society

(www.cancer.org)
National Kidney Foundation

(www.kidney.org)
Kidney Cancer Association

(www.kidneycancerassociation.org)


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