INTRODUCTION — Chronic lymphocytic leukemia, often referred to as CLL, is a type of cancer of the blood. It is one of a group of diseases that affects a type of white blood cell called a lymphocyte. The lymphocytes help the body fight infection.
In CLL, abnormally high numbers of ineffective lymphocytes are found in the blood and/or bone marrow (the spongy area in the middle of large bones where blood cells are formed). They cannot fight infection as normal lymphocytes do, and collect in increased numbers in lymph nodes and other areas, such as the liver and spleen. Their high numbers can cause them to interfere with the proper production of other blood cells, such as red cells and platelets.
Unlike acute lymphoblastic leukemia, which is fatal if left untreated, CLL is usually characterized by a slow progression of the disease and related symptoms. In many cases, it causes the patient little, if any, problems in its early stages. Patients may live with CLL for decades. Many times, it is diagnosed by blood tests that are performed during a routine physical exam. In other cases, symptoms may bring the patient to the doctor.
Careful analysis of the patient's blood and physical condition help the doctor determine the stage of the disease - a crucial first step in deciding on the proper course of treatment. Unlike patients with many other types of cancer, some patients with CLL may not benefit from early, aggressive treatment, but rather, may do better with careful long-term monitoring of the disease without treatment.
STAGING OF CLL — The natural history of CLL may vary considerably from person to person. Some patients may become sick within a short time of diagnosis; others live comfortably for years without problems. Determining which patients are most likely to get sick, and therefore are most likely to benefit from treatment of the disease, has been a challenge for doctors.
Two systems for staging CLL are now in use. They are used as a way to help identify patients with more serious versus "smoldering" disease, and as a way to help identify which patients are most likely to develop serious problems in the near term.
The Rai system — The Rai system is based on an analysis of how the body is affected by the abnormal lymphocytes. There are five stages. The higher numbers indicate a more advanced stage of disease: Stage 0: Increased numbers of abnormal lymphocytes are found in the blood or bone marrow; lymph nodes/organs are not swollen, and production of red cells and platelets is normal Stage I: Increased abnormal lymphocytes and enlarged lymph nodes Stage II: Increased abnormal lymphocytes with enlarged liver or spleen, with or without enlarged lymph nodes Stage III: Increased abnormal lymphocytes with anemia (low red blood cell count), with or without an enlarged spleen, liver, or lymph nodes Stage IV: Increased abnormal lymphocytes with a low platelet count, with or without anemia, enlarged liver, spleen, or lymph nodes
The Binet system — This system considers the five possible sites where lymphocytes can collect (lymph nodes in the neck, armpit, and groin, and lymphocyte-containing channels in the spleen and liver), and also on whether or not anemia or low platelet counts are present. There are three stages: Stage A: Fewer than three involved sites Stage B: Three or more involved sites Stage C: Presence of anemia or low platelet counts
Experts have recommended that these two systems be used together to define the stage of leukemia, for example, stage A0, A1, AII, BI, and so on. However, many clinicians still use either the Rai or Binet method.
What the stages mean — Staging helps doctors decide how likely it is that the person is soon to develop serious problems related to the CLL. Patients at Rai stage 0 are considered at low risk, those at stages I or II are at intermediate risk, and those at stage III or IV are at high risk. Similarly, patients characterized according to the Binet system have progressively increasing risk, with Stage A as the lowest and Stage C as the highest risk group. Average survivals for these three risk categories are: Low risk — 12 years Intermediate risk — 7.5 years High risk — 1.5 years
In general, doctors are more certain about expected disease progression in the higher versus the lower risk groups. That is, it is more difficult to tell which patients in the lower risk groups are most likely to go on to develop more serious disease. Research is underway to identify factors associated with a more aggressive course. For example, analysis of certain aspects of bone marrow cells and comparison of the patient's blood test results over time may prove helpful in identifying which patients in the lower risk groups are more likely to become ill with CLL.
Indications for treatment — As noted above, treatment is not always required for CLL. Some studies have shown that patients with so-called "smoldering" CLL are no more likely to die than a normal person of similar age and sex. Although treatment can be effective in controlling progression of the disease and alleviating symptoms, it usually does not produce a cure. This means that doctors and patients must carefully weigh the risks and discomforts of treatment against expected benefits to be gained.
However, there are certain groups of patients in whom some type of treatment is generally indicated. This includes patients with: Anemia and/or low platelets (Rai stages III or IV, or Binet stage C) Disease-related symptoms such as weakness, night sweats, weight loss, painful lymph node swelling, or fever Progressive disease, as demonstrated by rapidly increasing white cells in the blood, and/or rapidly enlarging lymph nodes, spleen, or liver Repeated infections
In some cases, especially in younger patients, doctors may recommend treating patients who do not have symptoms and/or those with low risk disease. Patients and doctors may choose to aggressively treat these milder forms of the disease in the hopes of obtaining long-term benefits and possibly a cure. Such aggressive treatments, such as bone marrow transplantation, may have serious side effects, and are generally part of a formal research study.
In other cases, detailed examination of the leukemic cells may be able to determine the future clinical course of the disease (ie, the prognosis), as well as the suitability of one or more treatment options. Such studies are the subject of a large number of ongoing research trials.
A number of different forms of treatment may be proposed. These are outlined in the following sections.
CHEMOTHERAPY — Chemotherapy, or the use of medications to kill cancer cells, can be effective in treating CLL. Depending on factors such as the stage of illness, the patient's age, and symptoms, the goals of chemotherapy may vary. For example, in some cases the goal is to halt the progression of the disease and relieve symptoms. In other cases, medicines will be chosen that are designed to help induce a remission of the disease. A patient undergoing chemotherapy for CLL should talk with the doctor about the goals for treatment.
Some of the medicines that may be used are listed here. Ask your doctor for complete information about the specific medicines you will receive, whether or not you will need to be admitted to the hospital for therapy, and what side effects you should watch for.
Historical agents — The following three agents were among the first to be successfully used for the treatment of CLL:
Chlorambucil (Leukeran) — This is taken by mouth either daily or in a single dose given every three to four weeks. The most common side effects are anemia, low white blood cell counts (leading to risk for infection), and low platelet counts (increasing the risk for bleeding).
Cyclophosphamide (Cytoxan) — This medicine can be given by mouth or through an intravenous (IV) line. Side effects include low blood counts, nausea and vomiting, hair loss, and irritation of the urinary bladder.
Steroids — Some treatment programs call for the use of steroids such as prednisone to treat CLL. Side effects include increased susceptibility to infections, high blood glucose, gastrointestinal problems, muscle weakness, and psychiatric symptoms.
Newer agents — The following two agents have been shown to be clearly superior to the historical agents noted above. Fludarabine, in combination with cyclophosphamide, is the most potent combination regimen developed to date.
Fludarabine — This medicine is showing promise as a way to induce a partial or complete remission of the disease. It must be given intravenously. Major side effects are low blood counts and fever. Older patients seem to be more prone to serious side effects from this medicine, including an increased risk of severe infections.
Cladribine (2-CdA) — This is a medicine similar to fludarabine, with similar side effects.
BIOLOGIC THERAPIES
Monoclonal antibodies — Medicines called monoclonal antibodies may help treat CLL by attacking specific substances (antigens) on the surface of the leukemic cells. Examples include rituximab and alemtuzumab. Combinations of antibodies with such chemotherapeutic agents as prednisone, cytoxan, and/or fludarabine are achieving very high complete remission rates of long duration.
Immunotherapy — The availability of agents known as biologic response modifiers has led to investigation of these agents in the treatment of CLL. Examples include recombinant interferon alfa or interleukin-2. These medicines may boost the patient's immune response so that it can more effectively fight the cancer.
RADIATION THERAPY — Radiation therapy may be used to shrink large, bulky masses of lymphoid tissue that occur because of accumulation of leukemic cells. These cells are very responsive to radiation and usually shrink considerably, although the swelling may return. The spleen or other areas of the body may be treated.
REMOVAL OF THE SPLEEN — Patients with CLL who have significant enlargement of the spleen often respond well to chemotherapy. In patients with persistent enlargement of the spleen, radiation therapy may be prescribed, but removal of the spleen is more likely to provide longer lasting benefits, including improvement in low red cell and platelet counts. If the patient is well enough to withstand surgery, removal of the spleen may be recommended.
BONE MARROW TRANSPLANTATION — Bone marrow transplantation (also called hematopoietic stem cell transplantation) is being more seriously considered as a therapy for CLL, especially for patients below the age of 55. Bone marrow transplant is a treatment in which the patient is given very high doses of chemotherapy or radiation, which kills cancer cells but also destroys all normal cells developing in the bone marrow. This means that the body's normal pipeline for replenishing critical blood components, the bone marrow, is no longer functional. After the treatment, the patient needs to have a healthy supply of very young blood cells, called stem cells, reintroduced, or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. (See "Patient information: Overview of bone marrow transplantation").
There are two main types of stem cell transplant: allogeneic and autologous.
Allogeneic transplant — In allogeneic transplant, the healthy cells that the patient receives following the high dose chemotherapy or radiation come from a donor, ideally a brother or sister with a similar genetic make-up. If the patient doesn't have a "matched" sibling, an unrelated person with a partially similar genetic makeup may be used.
Patients whose disease has become life-threatening but who are unable to tolerate high dose chemotherapy may be candidates for a reduced intensity transplant (called a mini-transplant or non-ablative transplant) from a relative or a matched unrelated donor, and may achieve long term control of their CLL.
Autologous transplant — In autologous transplant, the patient's own stem cells are removed before the high dose chemotherapy or radiation is given. In some cases, the cells are treated in order to remove any lingering leukemic cells that may be present, then they are frozen for storage. After the patient's chemotherapy or radiation is complete, the harvested cells are thawed and returned to the patient.
POSTPONING TREATMENT — As noted above, treatment of CLL is not appropriate for all patients. In a patient whose disease is not progressing rapidly, or in whom there are no troubling symptoms, the risks and discomforts of treatment may be greater than any possible benefit. In these cases, doctors will advise the patient to return for blood tests and a physical exam every three months. At the end of a year, it should be clear whether or not the patient has an aggressive form of the disease that requires treatment.
TREATMENT OF COMPLICATIONS — The major complications of CLL are caused by the low blood counts and immune system problems that either arise from the disease itself or the treatment. They include infection, anemia, and low platelets.
Infection — Episodes of infection are major complications that occur during the treatment of CLL. Infection is often related to low levels of important infection fighting proteins called gamma globulins. For this reason, patients who have repeated infections may be treated with intravenous immune globulin (IGIV, IVIG) to decrease the chance of infection. Infections of the upper respiratory tract are common, but usually respond to antibiotics. Some patients may develop chronic sinusitis.
Patients treated with certain chemotherapy agents may develop low white blood cells counts, and an increased risk of other infections. Early treatment with antibiotics is recommended, and, in some cases, medications that promote the growth of new blood cells may be given to boost the white cell count and decrease the infection risk.
Anemia — Anemia, or low red blood cell counts, is common in CLL. Red blood cells are needed to carry oxygen to all the cells in the body. Patients with anemia may experience fatigue, weakness, and chest pain. Treatment includes blood transfusion and, in some cases, administration of a medicine called erythropoietin, which can boost the red cell count in patients with certain types of anemia. Other forms of anemia may be treated with steroids.
Low platelet counts — Platelets are important components of the blood's clotting mechanism. Without adequate numbers of platelets, internal and external bleeding can occur. Patients with CLL and low platelet counts may see their counts improve with treatment of the CLL. In some cases, platelet transfusions are needed. Removal of the spleen, use of steroids, or agents which suppress the immune response as part of the treatment for CLL usually results in improved platelet counts.
Psychological aspects — Patients with CLL are forced to live with the uncertainties associated with a chronic illness. In some cases, it is puzzling and frightening to hear that there is a diagnosis of leukemia and that no treatment is recommended. Patients and their healthcare providers must speak frequently and honestly to deal with fears and clarify any misunderstandings about this sometimes confusing disease. Some patients and families benefit from psychological counseling to help them cope with the strong emotions that can accompany this diagnosis.
THE ROLE OF CLINICAL TRIALS — Many patients with leukemia will be asked about enrolling in a clinical (research) trial. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask your doctor for more information, or read about clinical trials at:
http://cancernet.nci.nih.gov/clinicaltrials
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)
National Cancer Institute
(www.cancer.gov/cancer_information/)
American Cancer Society
(www.cancer.org)
The Leukemia & Lymphoma Society
(www.leukemia-lymphoma.org)
National Marrow Donor Program
(www.marrow.org)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
[1-8]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Call, TG, Phyliky, RL, Noel, P, et al. Incidence of chronic lymphocytic leukemia in Olmsted County, Minnesota, 1935 through 1989, with emphasis on changes in initial stage at diagnosis. Mayo Clin Proc 1994; 69:323.
2. Rai, KR, Sawitsky, A, Cronkite, EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46:219.
3. Binet, L-L, Auquier, A, Dighiero, G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48:198.
4. Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on Chronic Lymphocytic Leukemia. Ann Intern Med 1989; 110:236.
5. Keating, MJ, Kantarjian, H, Talpaz, M, et al. Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 1989; 74:19.
6. Seymour, JF, Cusack, JD, Lerner, SA, et al. Case/control study of the role of splenectomy in chronic lymphocytic leukemia. J Clin Oncol 1997; 15:52.
7. Khouri, IF, Keating, MJ, Vriesendorp, HM, et al. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia. J Clin Oncol 1994; 12:748.
8. Johnson, S, Smith, AG, Loffler, H, et al. Multicenter prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet 1996; 347:1432.
Friday, October 12, 2007
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)
[1-7]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Fisher, RI, Rosenberg, SA, Fyfe, G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000; 6 Suppl 1:S55.
2. Escudier, B, Eisen, T, Stadler, WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125.
3. Motzer, RJ, Hutson, TE, Tomczak, P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115.
4. Eggener, SE, Yossepowitch, O, Pettus, JA, et al. Renal cell carcinoma recurrence after nephrectomy for localized disease: predicting survival from time of recurrence. J Clin Oncol 2006; 24:3101.
5. Ono, Y, Hattori, R, Gotoh, M, et al. Laparoscopic radical nephrectomy for renal cell carcinoma: the standard of care already?. Curr Opin Urol 2005; 15:75.
6. Pantuck, AJ, Zisman, A, Dorey, F, et al. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer 2003; 97:2995.
7. McDermott, DF, Regan, MM, Clark, JI, et al. Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol 2005; 23:133.
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)
[1-7]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Fisher, RI, Rosenberg, SA, Fyfe, G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000; 6 Suppl 1:S55.
2. Escudier, B, Eisen, T, Stadler, WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125.
3. Motzer, RJ, Hutson, TE, Tomczak, P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115.
4. Eggener, SE, Yossepowitch, O, Pettus, JA, et al. Renal cell carcinoma recurrence after nephrectomy for localized disease: predicting survival from time of recurrence. J Clin Oncol 2006; 24:3101.
5. Ono, Y, Hattori, R, Gotoh, M, et al. Laparoscopic radical nephrectomy for renal cell carcinoma: the standard of care already?. Curr Opin Urol 2005; 15:75.
6. Pantuck, AJ, Zisman, A, Dorey, F, et al. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer 2003; 97:2995.
7. McDermott, DF, Regan, MM, Clark, JI, et al. Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol 2005; 23:133.
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)
[1-7]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Fisher, RI, Rosenberg, SA, Fyfe, G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000; 6 Suppl 1:S55.
2. Escudier, B, Eisen, T, Stadler, WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125.
3. Motzer, RJ, Hutson, TE, Tomczak, P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115.
4. Eggener, SE, Yossepowitch, O, Pettus, JA, et al. Renal cell carcinoma recurrence after nephrectomy for localized disease: predicting survival from time of recurrence. J Clin Oncol 2006; 24:3101.
5. Ono, Y, Hattori, R, Gotoh, M, et al. Laparoscopic radical nephrectomy for renal cell carcinoma: the standard of care already?. Curr Opin Urol 2005; 15:75.
6. Pantuck, AJ, Zisman, A, Dorey, F, et al. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer 2003; 97:2995.
7. McDermott, DF, Regan, MM, Clark, JI, et al. Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol 2005; 23:133.
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)
[1-7]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Fisher, RI, Rosenberg, SA, Fyfe, G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000; 6 Suppl 1:S55.
2. Escudier, B, Eisen, T, Stadler, WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125.
3. Motzer, RJ, Hutson, TE, Tomczak, P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115.
4. Eggener, SE, Yossepowitch, O, Pettus, JA, et al. Renal cell carcinoma recurrence after nephrectomy for localized disease: predicting survival from time of recurrence. J Clin Oncol 2006; 24:3101.
5. Ono, Y, Hattori, R, Gotoh, M, et al. Laparoscopic radical nephrectomy for renal cell carcinoma: the standard of care already?. Curr Opin Urol 2005; 15:75.
6. Pantuck, AJ, Zisman, A, Dorey, F, et al. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy. Cancer 2003; 97:2995.
7. McDermott, DF, Regan, MM, Clark, JI, et al. Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol 2005; 23:133.
Renal biopsy
INTRODUCTION — A renal biopsy is a procedure in which a sample of kidney (also called renal) tissue is obtained. Microscopic examination of the tissue can provide information needed to diagnose, monitor or treat a renal disorder.
REASONS FOR BIOPSY — Renal biopsy is recommended for selected patients with kidney disease. It is most commonly performed when less invasive measures are insufficient. The following are examples of the most common reasons for biopsy:
Hematuria with renal disease — Hematuria (blood in the urine) can occur with a number of conditions that affect the kidneys and urinary tract. While renal biopsy is not indicated in all cases of hematuria, it may be performed in those with hematuria as well as progressive renal disease (such as increasing proteinuria or blood pressure). (See "Patient information: Blood in the urine (hematuria)").
Proteinuria — Proteinuria (protein in the urine) occurs in many patients with renal conditions. Renal biopsy is usually reserved for patients with relatively high or increasing levels of proteinuria or for patients who have proteinuria along with other signs of renal dysfunction.
A patient with nephrotic syndrome (significant proteinuria, low blood albumin level, and edema (swelling) of the arms and legs) may need a renal biopsy, especially if the patient has systemic lupus erythematosus (SLE). Other patients with nephrotic syndrome may require a renal biopsy, depending upon the suspected cause of the nephrotic syndrome. (See "Patient information: Protein in the urine (proteinuria)" and see "Patient information: The nephrotic syndrome").
Acute renal failure — Renal failure refers to kidney injury that impairs kidney function. It can occur abruptly (called acute renal failure) or progress over a period of time (called chronic renal failure). The cause of acute renal failure can usually be determined without renal biopsy. Biopsy is performed in those instances when the cause is uncertain.
Acute nephritic syndrome — Patients with acute nephritic syndrome have hematuria, proteinuria, high blood pressure, and impaired renal function. Renal biopsy may be recommended to determine the cause of nephritic syndrome unless it can be determined through blood testing.
PROCEDURE
Preparation — Testing may be done before the biopsy to ensure that there is no evidence of infection or a blood clotting abnormality. The biopsy is usually performed while the patient is awake, after receiving an injection of local anesthesia (numbing medicine) to minimize pain.
To decrease the risk of bleeding, patients are usually advised to avoid medicines that increase the risk of bleeding (such as aspirin or nonsteroidal antiinflammatory drugs (ibuprofen, naproxen)) for one to two weeks before the biopsy. If the patient takes warfarin or heparin (drugs that impair clotting and increase the risk of bleeding), the physician will give specific instructions about the dose and time to take these medications before surgery.
Biopsy procedure — In most cases, an ultrasound is done to guide the physician inserting the needle. Less commonly, computed tomography (CT scan) guidance is used. The needle is inserted through the skin in the back and into the kidney. Once the needle is in contact with the kidney, a sample of renal tissue is withdrawn.
In some patients, a different approach may be used to perform the biopsy. In this case, the patient is sedated and a small skin incision is made to obtain the sample of kidney tissue; this procedure is called open renal biopsy.
Following the biopsy, the patient is kept in the post-operative recovery unit for several hours to monitor for potential complications, including pain and bleeding.
COMPLICATIONS — Serious complications of renal biopsy are rare.
Bleeding — Bleeding is the most common complication of renal biopsy. Rarely, bleeding is severe enough to require a blood transfusion or surgery. Most patients who undergo renal biopsy notice blood in the urine for several days after the procedure. Patients with urine that is bright red or brown for longer than one week should consult with their healthcare provider.
Pain — Pain is a common problem, although it is usually mild to moderate and resolves within a few hours. Medications can be given to reduce pain after the procedure. Patients who experience severe or prolonged pain should notify their healthcare provider; this can be a sign of a blood clot that is obstructing the ureter (tube that leads to the bladder) or a large hematoma (a mass of clotted blood) that stretches the kidney.
Arteriovenous fistula — Damage caused by the biopsy needle to the walls of an adjacent artery and vein can lead to a fistula (a connection between the two blood vessels). Fistulas generally do not cause problems and usually close on their own over time.
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)
National Institute of Diabetes and Digestive and Kidney Diseases
(www.niddk.nih.gov)
National Kidney Foundation
(www.kidney.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Madaio, MP. Renal biopsy. Kidney Int 1990; 38:529.
2. Appel, GB. Renal biopsy: How effective, what technique, and how safe. J Nephrol 1993; 6:4.
3. Stiles, KP, Yuan, CM, Chung, EM, et al. Renal biopsy in high-risk patients with medical diseases of the kidney. Am J Kidney Dis 2000; 36:419.
4. Parrish, AE. Complications of percutaneous renal biopsy: A review of 37 years' experience. Clin Nephrol 1992; 38:135.
REASONS FOR BIOPSY — Renal biopsy is recommended for selected patients with kidney disease. It is most commonly performed when less invasive measures are insufficient. The following are examples of the most common reasons for biopsy:
Hematuria with renal disease — Hematuria (blood in the urine) can occur with a number of conditions that affect the kidneys and urinary tract. While renal biopsy is not indicated in all cases of hematuria, it may be performed in those with hematuria as well as progressive renal disease (such as increasing proteinuria or blood pressure). (See "Patient information: Blood in the urine (hematuria)").
Proteinuria — Proteinuria (protein in the urine) occurs in many patients with renal conditions. Renal biopsy is usually reserved for patients with relatively high or increasing levels of proteinuria or for patients who have proteinuria along with other signs of renal dysfunction.
A patient with nephrotic syndrome (significant proteinuria, low blood albumin level, and edema (swelling) of the arms and legs) may need a renal biopsy, especially if the patient has systemic lupus erythematosus (SLE). Other patients with nephrotic syndrome may require a renal biopsy, depending upon the suspected cause of the nephrotic syndrome. (See "Patient information: Protein in the urine (proteinuria)" and see "Patient information: The nephrotic syndrome").
Acute renal failure — Renal failure refers to kidney injury that impairs kidney function. It can occur abruptly (called acute renal failure) or progress over a period of time (called chronic renal failure). The cause of acute renal failure can usually be determined without renal biopsy. Biopsy is performed in those instances when the cause is uncertain.
Acute nephritic syndrome — Patients with acute nephritic syndrome have hematuria, proteinuria, high blood pressure, and impaired renal function. Renal biopsy may be recommended to determine the cause of nephritic syndrome unless it can be determined through blood testing.
PROCEDURE
Preparation — Testing may be done before the biopsy to ensure that there is no evidence of infection or a blood clotting abnormality. The biopsy is usually performed while the patient is awake, after receiving an injection of local anesthesia (numbing medicine) to minimize pain.
To decrease the risk of bleeding, patients are usually advised to avoid medicines that increase the risk of bleeding (such as aspirin or nonsteroidal antiinflammatory drugs (ibuprofen, naproxen)) for one to two weeks before the biopsy. If the patient takes warfarin or heparin (drugs that impair clotting and increase the risk of bleeding), the physician will give specific instructions about the dose and time to take these medications before surgery.
Biopsy procedure — In most cases, an ultrasound is done to guide the physician inserting the needle. Less commonly, computed tomography (CT scan) guidance is used. The needle is inserted through the skin in the back and into the kidney. Once the needle is in contact with the kidney, a sample of renal tissue is withdrawn.
In some patients, a different approach may be used to perform the biopsy. In this case, the patient is sedated and a small skin incision is made to obtain the sample of kidney tissue; this procedure is called open renal biopsy.
Following the biopsy, the patient is kept in the post-operative recovery unit for several hours to monitor for potential complications, including pain and bleeding.
COMPLICATIONS — Serious complications of renal biopsy are rare.
Bleeding — Bleeding is the most common complication of renal biopsy. Rarely, bleeding is severe enough to require a blood transfusion or surgery. Most patients who undergo renal biopsy notice blood in the urine for several days after the procedure. Patients with urine that is bright red or brown for longer than one week should consult with their healthcare provider.
Pain — Pain is a common problem, although it is usually mild to moderate and resolves within a few hours. Medications can be given to reduce pain after the procedure. Patients who experience severe or prolonged pain should notify their healthcare provider; this can be a sign of a blood clot that is obstructing the ureter (tube that leads to the bladder) or a large hematoma (a mass of clotted blood) that stretches the kidney.
Arteriovenous fistula — Damage caused by the biopsy needle to the walls of an adjacent artery and vein can lead to a fistula (a connection between the two blood vessels). Fistulas generally do not cause problems and usually close on their own over time.
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)
National Institute of Diabetes and Digestive and Kidney Diseases
(www.niddk.nih.gov)
National Kidney Foundation
(www.kidney.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Madaio, MP. Renal biopsy. Kidney Int 1990; 38:529.
2. Appel, GB. Renal biopsy: How effective, what technique, and how safe. J Nephrol 1993; 6:4.
3. Stiles, KP, Yuan, CM, Chung, EM, et al. Renal biopsy in high-risk patients with medical diseases of the kidney. Am J Kidney Dis 2000; 36:419.
4. Parrish, AE. Complications of percutaneous renal biopsy: A review of 37 years' experience. Clin Nephrol 1992; 38:135.
Renal biopsy
INTRODUCTION — A renal biopsy is a procedure in which a sample of kidney (also called renal) tissue is obtained. Microscopic examination of the tissue can provide information needed to diagnose, monitor or treat a renal disorder.
REASONS FOR BIOPSY — Renal biopsy is recommended for selected patients with kidney disease. It is most commonly performed when less invasive measures are insufficient. The following are examples of the most common reasons for biopsy:
Hematuria with renal disease — Hematuria (blood in the urine) can occur with a number of conditions that affect the kidneys and urinary tract. While renal biopsy is not indicated in all cases of hematuria, it may be performed in those with hematuria as well as progressive renal disease (such as increasing proteinuria or blood pressure). (See "Patient information: Blood in the urine (hematuria)").
Proteinuria — Proteinuria (protein in the urine) occurs in many patients with renal conditions. Renal biopsy is usually reserved for patients with relatively high or increasing levels of proteinuria or for patients who have proteinuria along with other signs of renal dysfunction.
A patient with nephrotic syndrome (significant proteinuria, low blood albumin level, and edema (swelling) of the arms and legs) may need a renal biopsy, especially if the patient has systemic lupus erythematosus (SLE). Other patients with nephrotic syndrome may require a renal biopsy, depending upon the suspected cause of the nephrotic syndrome. (See "Patient information: Protein in the urine (proteinuria)" and see "Patient information: The nephrotic syndrome").
Acute renal failure — Renal failure refers to kidney injury that impairs kidney function. It can occur abruptly (called acute renal failure) or progress over a period of time (called chronic renal failure). The cause of acute renal failure can usually be determined without renal biopsy. Biopsy is performed in those instances when the cause is uncertain.
Acute nephritic syndrome — Patients with acute nephritic syndrome have hematuria, proteinuria, high blood pressure, and impaired renal function. Renal biopsy may be recommended to determine the cause of nephritic syndrome unless it can be determined through blood testing.
PROCEDURE
Preparation — Testing may be done before the biopsy to ensure that there is no evidence of infection or a blood clotting abnormality. The biopsy is usually performed while the patient is awake, after receiving an injection of local anesthesia (numbing medicine) to minimize pain.
To decrease the risk of bleeding, patients are usually advised to avoid medicines that increase the risk of bleeding (such as aspirin or nonsteroidal antiinflammatory drugs (ibuprofen, naproxen)) for one to two weeks before the biopsy. If the patient takes warfarin or heparin (drugs that impair clotting and increase the risk of bleeding), the physician will give specific instructions about the dose and time to take these medications before surgery.
Biopsy procedure — In most cases, an ultrasound is done to guide the physician inserting the needle. Less commonly, computed tomography (CT scan) guidance is used. The needle is inserted through the skin in the back and into the kidney. Once the needle is in contact with the kidney, a sample of renal tissue is withdrawn.
In some patients, a different approach may be used to perform the biopsy. In this case, the patient is sedated and a small skin incision is made to obtain the sample of kidney tissue; this procedure is called open renal biopsy.
Following the biopsy, the patient is kept in the post-operative recovery unit for several hours to monitor for potential complications, including pain and bleeding.
COMPLICATIONS — Serious complications of renal biopsy are rare.
Bleeding — Bleeding is the most common complication of renal biopsy. Rarely, bleeding is severe enough to require a blood transfusion or surgery. Most patients who undergo renal biopsy notice blood in the urine for several days after the procedure. Patients with urine that is bright red or brown for longer than one week should consult with their healthcare provider.
Pain — Pain is a common problem, although it is usually mild to moderate and resolves within a few hours. Medications can be given to reduce pain after the procedure. Patients who experience severe or prolonged pain should notify their healthcare provider; this can be a sign of a blood clot that is obstructing the ureter (tube that leads to the bladder) or a large hematoma (a mass of clotted blood) that stretches the kidney.
Arteriovenous fistula — Damage caused by the biopsy needle to the walls of an adjacent artery and vein can lead to a fistula (a connection between the two blood vessels). Fistulas generally do not cause problems and usually close on their own over time.
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)
National Institute of Diabetes and Digestive and Kidney Diseases
(www.niddk.nih.gov)
National Kidney Foundation
(www.kidney.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Madaio, MP. Renal biopsy. Kidney Int 1990; 38:529.
2. Appel, GB. Renal biopsy: How effective, what technique, and how safe. J Nephrol 1993; 6:4.
3. Stiles, KP, Yuan, CM, Chung, EM, et al. Renal biopsy in high-risk patients with medical diseases of the kidney. Am J Kidney Dis 2000; 36:419.
4. Parrish, AE. Complications of percutaneous renal biopsy: A review of 37 years' experience. Clin Nephrol 1992; 38:135.
REASONS FOR BIOPSY — Renal biopsy is recommended for selected patients with kidney disease. It is most commonly performed when less invasive measures are insufficient. The following are examples of the most common reasons for biopsy:
Hematuria with renal disease — Hematuria (blood in the urine) can occur with a number of conditions that affect the kidneys and urinary tract. While renal biopsy is not indicated in all cases of hematuria, it may be performed in those with hematuria as well as progressive renal disease (such as increasing proteinuria or blood pressure). (See "Patient information: Blood in the urine (hematuria)").
Proteinuria — Proteinuria (protein in the urine) occurs in many patients with renal conditions. Renal biopsy is usually reserved for patients with relatively high or increasing levels of proteinuria or for patients who have proteinuria along with other signs of renal dysfunction.
A patient with nephrotic syndrome (significant proteinuria, low blood albumin level, and edema (swelling) of the arms and legs) may need a renal biopsy, especially if the patient has systemic lupus erythematosus (SLE). Other patients with nephrotic syndrome may require a renal biopsy, depending upon the suspected cause of the nephrotic syndrome. (See "Patient information: Protein in the urine (proteinuria)" and see "Patient information: The nephrotic syndrome").
Acute renal failure — Renal failure refers to kidney injury that impairs kidney function. It can occur abruptly (called acute renal failure) or progress over a period of time (called chronic renal failure). The cause of acute renal failure can usually be determined without renal biopsy. Biopsy is performed in those instances when the cause is uncertain.
Acute nephritic syndrome — Patients with acute nephritic syndrome have hematuria, proteinuria, high blood pressure, and impaired renal function. Renal biopsy may be recommended to determine the cause of nephritic syndrome unless it can be determined through blood testing.
PROCEDURE
Preparation — Testing may be done before the biopsy to ensure that there is no evidence of infection or a blood clotting abnormality. The biopsy is usually performed while the patient is awake, after receiving an injection of local anesthesia (numbing medicine) to minimize pain.
To decrease the risk of bleeding, patients are usually advised to avoid medicines that increase the risk of bleeding (such as aspirin or nonsteroidal antiinflammatory drugs (ibuprofen, naproxen)) for one to two weeks before the biopsy. If the patient takes warfarin or heparin (drugs that impair clotting and increase the risk of bleeding), the physician will give specific instructions about the dose and time to take these medications before surgery.
Biopsy procedure — In most cases, an ultrasound is done to guide the physician inserting the needle. Less commonly, computed tomography (CT scan) guidance is used. The needle is inserted through the skin in the back and into the kidney. Once the needle is in contact with the kidney, a sample of renal tissue is withdrawn.
In some patients, a different approach may be used to perform the biopsy. In this case, the patient is sedated and a small skin incision is made to obtain the sample of kidney tissue; this procedure is called open renal biopsy.
Following the biopsy, the patient is kept in the post-operative recovery unit for several hours to monitor for potential complications, including pain and bleeding.
COMPLICATIONS — Serious complications of renal biopsy are rare.
Bleeding — Bleeding is the most common complication of renal biopsy. Rarely, bleeding is severe enough to require a blood transfusion or surgery. Most patients who undergo renal biopsy notice blood in the urine for several days after the procedure. Patients with urine that is bright red or brown for longer than one week should consult with their healthcare provider.
Pain — Pain is a common problem, although it is usually mild to moderate and resolves within a few hours. Medications can be given to reduce pain after the procedure. Patients who experience severe or prolonged pain should notify their healthcare provider; this can be a sign of a blood clot that is obstructing the ureter (tube that leads to the bladder) or a large hematoma (a mass of clotted blood) that stretches the kidney.
Arteriovenous fistula — Damage caused by the biopsy needle to the walls of an adjacent artery and vein can lead to a fistula (a connection between the two blood vessels). Fistulas generally do not cause problems and usually close on their own over time.
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)
National Institute of Diabetes and Digestive and Kidney Diseases
(www.niddk.nih.gov)
National Kidney Foundation
(www.kidney.org)
[1-4]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Madaio, MP. Renal biopsy. Kidney Int 1990; 38:529.
2. Appel, GB. Renal biopsy: How effective, what technique, and how safe. J Nephrol 1993; 6:4.
3. Stiles, KP, Yuan, CM, Chung, EM, et al. Renal biopsy in high-risk patients with medical diseases of the kidney. Am J Kidney Dis 2000; 36:419.
4. Parrish, AE. Complications of percutaneous renal biopsy: A review of 37 years' experience. Clin Nephrol 1992; 38:135.
Genetic testing for breast and ovarian cancer
INTRODUCTION — Many women feel anxious about their chance of developing breast or ovarian cancer, particularly if they have one or several close relatives with either condition. Women who have a family history of breast or ovarian cancer often wish to know if they have inherited a tendency to develop these tumors, and if so, what their lifetime risk is of developing breast or ovarian cancer.
Other women with a personal history of breast cancer, particularly if it was diagnosed at a young age, may worry that if they have inherited a tendency to develop breast and/or ovarian cancer, it may be passed on to their children.
Inherited mutations in two genes (known as BRCA1 and BRCA2) have been shown to increase the risk of both breast cancer and ovarian cancer. Genetic testing is available that may identify individuals who have inherited an altered form of one of these genes that increases the risk of breast and/or ovarian cancer. Patients who test positive can consider intensified screening or interventions to decrease the risk of cancer (medications or surgical removal of the breasts, ovaries, or both).
However, genetic testing for BRCA mutations is imperfect. Most women with a family history of breast cancer have not inherited one of these two abnormal genes, and not all women who have inherited one of these genes will develop cancer. Furthermore, the results of BRCA testing may be confusing, and do not always lead to a clear action plan. Genetic testing for BRCA mutations can create emotional turmoil and family discord, and may have an impact on future medical care and insurability. Thus, it is important for the patient, her healthcare provider, and family members to carefully consider whether to undergo such testing.
This topic review will focus on which women should consider genetic testing for the presence of BRCA mutations, issues to consider before undergoing testing, and the available options for women who are found to carry one of these mutations.
Genetic testing is not an emergency procedure. Taking time to understand the complexities, and discussing questions with health-care professionals and family members can help to clarify expectations from testing and anticipate future issues.
GENETIC TESTING GOALS — Genetic testing for breast and/or ovarian cancer analyzes the composition of the BRCA genes to look for alterations (mutations) associated with breast and/or ovarian cancer.
How do genes relate to cancer? — A person's visible characteristics (such as hair and eye color) as well as other invisible properties (including predisposition to cancer and other diseases), are determined by his or her genetic "blueprint", which is inherited from both parents as 23 pairs of chromosomes. Each chromosome is made up of a long strand of DNA. Discrete segments or sections of the DNA (called genes) contain the information that is needed to construct specific proteins that carry out the specific function of the individual cells that make up the body. There are approximately 30,000 human genes distributed among the 23 pairs of human chromosomes.
Most of the time, genes function properly and the body develops and performs normally. However, when a gene is altered (often by a mutation or change in the chemical structure of the gene), it may not provide the right signals to the body's cells to carry out their normal functions. If the affected gene is normally involved in the regulation of cell growth, a mutated gene may result in signals that allow uncontrolled cell growth. This process of uncontrolled cell growth causes tumors such as breast cancer to grow unchecked within the body.
An inherited mutation (ie, one that is passed from parent to child, and is present in all cells at the time the child is born) is called a germline mutation. In contrast, a noninherited mutation (ie, one that comes about during a person's lifetime) is called an acquired mutation. Acquired mutations can be caused by exposure to environmental agents such as radiation, chemicals (including those found in tobacco smoke), or viruses; they may also happen spontaneously. Most human cancers are thought to be caused by acquired mutations.
Most breast cancers (at least 90 percent) are not related to inherited (germline) mutations. However, for those 5 to 10 percent that are due to germline mutations, BRCA1 and BRCA2 mutations are thought to account for the majority. These genes are called tumor suppressor genes, meaning that they normally function to keep the growth of the body's cells under control. When one of these genes becomes mutated, cell growth becomes unregulated, paving the way for the development of a cancer. Most scientists believe that a cancer develops only if additional genetic mutations are acquired.
Other genes — Besides BRCA1 and BRCA2, a few other genes have been identified that are associated with breast and/or ovarian cancer, but in general, these involve rare syndromes that are related to other medical conditions and cancer types. There are also likely other, not-yet-identified, genes that are involved in inherited breast and/or ovarian cancer. This topic review will focus only on the BRCA genes.
WHO SHOULD CONSIDER GENETIC TESTING? — Genetic testing should not be done in all women with a family history of breast and/or ovarian cancer since BRCA1 and BRCA2 mutations are rare. Determining which women should consider genetic testing involves examination of an individual's personal and family history of breast cancer and/or ovarian cancer.
BRCA mutations occur in approximately 0.1 percent of individuals (1 in 1000 people). However, some ethnic groups have a higher chance of inheriting one of these mutations. For example, about 2 percent of women of Ashkenazi Jewish (Eastern European) descent carry a BRCA1 or BRCA2 mutation, and between 12 and 30 percent of breast cancers in this group are thought to be caused by mutations in the BRCA1 or BRCA2 genes. These statistics do not consider a family history of breast and/or ovarian cancer.
Because germline mutations are rare, and testing for them can produce indeterminate results, testing is usually offered to women who are at a high risk of having a BRCA mutation. Tools are available (such as a computer program called BRCAPRO [1]) to estimate the likelihood of a woman having a BRCA mutation based on her individual and personal history. Typically, a woman's health care provider or a genetics counselor will ask a set of questions about a woman's personal and family history and plug the answers into this risk assessment tool. The program then calculates an estimate of the chances of finding a BRCA mutation based upon a number of risk assessment tools. Guidelines from national organizations suggest that if the estimated chance of inheriting one of these mutations is greater than 10 percent (one in ten), genetic testing may be appropriate.
However, current recommendations are moving away from numerical cut-off values for determining when genetic testing should be offered. Instead, many organizations advocate using more details of an individual's and family's history as a screening tool to identify women who should be considered for BRCA testing.
Family history patterns — Doctors and patients should be aware of family history patterns that are associated with a higher risk of a BRCA mutation. These include: Multiple relatives affected with breast and/or ovarian cancer, particularly if they were diagnosed at an early age (less than 50 years old) A relative with more than one cancer, such as breast cancer involving both breasts or breast and ovarian cancer Evidence that multiple generations of a family are affected.
Women who develop breast cancer before the age of 50 are more likely to have a mutation than those who develop breast cancer at an older age. If a young woman develops breast cancer and also has a family history of breast and/or ovarian cancer, her chance of carrying a mutation increases dramatically. Family history on the father's side is as important as maternal history.
When there is a strong family history of breast and/or ovarian cancer, BRCA testing should be done on the relative who has the cancer whenever possible. If a mutation is not found, it is usually not helpful to test unaffected relatives. If a relative with breast cancer tests positive for a BRCA mutation, genetic testing should be considered for all of her at-risk adult relatives (male and female).
TESTING PROCEDURE
Pre-test counseling — Genetic testing involves taking a sample of blood and sending it to a lab for testing. However, a woman must consider a number of factors before deciding to undergo genetic testing. These include medical, emotional, practical, and financial factors that can profoundly affect a woman and her family. Women who are considering genetic testing should discuss these issues with a certified genetic counselor, if possible, to understand what is involved in the process of genetic testing. A list of certified genetics counselors and their phone numbers is available through the National Cancer Institute [2].
An example of a consent form is presented in table 1 (show table 1A-1D), and briefly discussed below.
Emotional effects for patient — Although anxiety may cause some high-risk individuals to refuse genetic testing, the available data suggest that there are no major adverse psychological effects of learning the results of BRCA testing. In fact, data from families with hereditary cancer and from individuals who underwent genetic testing in clinic settings suggest less distress in members of high-risk families who test negative for a familial mutation.
While it is normal for individuals who test positive (mutation carriers) to experience some level of distress, anxiety, or sadness, most studies suggest that these individuals do not suffer serious psychological effects or significantly increased distress levels. For many individuals, learning about positive test results can also produce feelings of relief, as risk information is clarified and a plan for managing that risk can be put into place. Women who have less significant family histories and who do not expect to receive positive results may be more vulnerable to psychological problems or high levels of distress after BRCA testing. In families that have a known BRCA mutation, it is not unusual for women who test negative to experience "survivor's guilt" for being spared a burden that other relatives have to endure.
Effects on family members — A discussion of the implications of the test results for family members is an important component of counseling. This includes identifying at-risk family members and encouraging patients to share results with their relatives.
The decision to share test results with relatives and the ramifications of that decision can cause significant emotional strain and family discord. The role of information "gatekeeper" may be overwhelming for some women, particularly as they try to attend to their own needs for emotional support. Nevertheless, studies have found that most individuals, including carriers and non-carriers, opt to share their results with at-risk relatives. For many individuals who seek testing, gaining information for family members is one of the most important benefits of testing.
Costs and insurance coverage — Because the BRCA genes are large and include hundreds of different mutations, testing is expensive. Commercial charges by Myriad Genetics Laboratories® (which are subject to change) are as follows: Full BRCA1/2 testing, which includes testing for five large rearrangements in BRCA1 and for very high risk families, rearrangement testing in BRCA1 and BRCA2 — $3120 Once a mutation is identified in an affected individual, analysis for the specific mutation in relatives costs $385 Analysis of the three specific mutations most commonly seen in Ashkenazi Jewish individuals is $460
A list of testing laboratories is available through the Gene Tests website, at www.genetests.org (click on "Laboratory Directory"). However, full sequencing is provided in the United States by only one commercial laboratory, Myriad Genetic Laboratories®. Genetic testing for BRCA1 and BRCA2 is very expensive, but in the United States, most health insurance companies will cover 80 percent or more of the costs. In many instances, a letter of medical necessity is required from a physician or genetic counselor to demonstrate the potential impact of a positive test result on future care (eg, whether a positive result will be used to intensify screening efforts or recommend surgery). Many people are concerned about the possibility of health insurance discrimination if they have a positive result from a genetic test. This phenomenon has been difficult to document. Two types of insurance may be affected for patients who test positive: the person's health insurance and their life insurance.
The 1996 Health Insurance Portability and Accountability Act (HIPAA) contains provisions to protect individuals with group insurance from having their individual health insurance premiums raised or canceled because of a preexisting condition, including a genetic test result. Some state laws also provide protection. However, there are loopholes that do not cover people with individual (private) insurance and those applying for life insurance. Several websites are available that provide additional information on this subject [3,4]. The effect of a positive genetic test on the ability to obtain life insurance is less clear. Presently there are no federal laws addressing this issue.
Options for treatment if a mutation is identified — Before a genetic test is done, it is important that the woman understand her options for treatment (see "Options after testing positive" below).
Post-test counseling — It is a good idea to schedule an in-person meeting with a genetics counselor or physician to receive the genetic testing results. During this meeting, test results will be explained. This is an excellent time to bring up any questions related to the testing technique or reliability of results.
During the post-test counseling session, patients should review the possible implications of test results on family members. Patients are encouraged to share their results with family members.
INTERPRETING THE RESULTS — Interpretation of test results is not always clear cut. A negative test does not mean that a woman will never develop cancer; nor does a positive test mean that she will definitely develop cancer.
The easiest tests to interpret are those done after a mutation has already been identified in one or more close relatives who have breast and/or ovarian cancer. A positive result occurs when an individual tests positive for the same mutation as their relatives. A negative result occurs when an individual tests negative for a mutation that has already been identified in their family.
If an affected high-risk individual is the first to be tested in a specific family, results may be less clear. There are a number of possible results: A mutation could be present in BRCA1 or BRCA2 but was not detected by available methods A mutation in another risk-conferring gene that is rare and/or not yet identified could be present The individual being tested could have developed a sporadic (noninherited) rather than hereditary cancer. Another possibility is that a BRCA1 or BRCA2 alteration may be identified that is considered to be a "variant of uncertain significance." This means that it could possibly be a newly identified deleterious mutation or it could simply be a normal change in the gene. Such changes appear to be more common in certain ethnic groups, such as African-Americans. Further research will clarify the significance of many of these changes.
OPTIONS AFTER TESTING POSITIVE — Usually, women who test positive for a BRCA mutation are referred to specialists who can review their options. Several alternatives are available for women who are at increased risk for breast and ovarian cancer: increased surveillance (screening) for breast and ovarian cancer, preventive surgery, and/or the use of medications to reduce the risk of cancer (called chemoprevention). Cancer risk might best be decreased through a combination of some or all of these methods (show table 2). Women considering genetic testing should discuss the table with their healthcare provider.
Intensified breast cancer screening — Women who have inherited BRCA1 or BRCA2 mutations are recommended to increase the level and frequency of screening strategies as follows: Monthly breast self-examination (BSE) beginning at age 18; women should be specifically instructed on how to perform BSE) Clinical breast examination two to four times annually beginning at age 25 Annual mammography beginning at age 25; in some women, mammography may be recommended every 6 months Annual breast MRI to take place approximately 6 months after the annual mammogram. Magnetic resonance imaging (MRI) uses a strong magnet rather than x-rays or radiation to create a detailed image of a part of the body. Breast MRI appears to be more sensitive than screening mammogram for detecting early breast cancers in high-risk women, and several experts groups (including the National Comprehensive Cancer Network and the American Cancer Society) now recommend annual breast MRI for these women.
However, there are insufficient data to recommend breast MRI instead of screening mammography in any group of women. One reason is that MRI does not appear to be as sensitive for diagnosing conditions such as ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer.
Despite these recommendations by several expert groups, studies do not definitively prove that intensive screening improves cancer outcomes in women who inherit BRCA mutations. A major problem is that many of the screening tests are not sensitive enough to pick up early cancers at a time when they are most likely to be cured.
Ovarian cancer screening
High risk women — Women who have inherited a BRCA mutation have an increased risk of developing ovarian cancer and may benefit from tests to detect it at an early stage. However, unlike screening for breast cancer, screening tests for ovarian cancer are not very accurate in detecting disease. These tests have suboptimal sensitivity (ability to detect early ovarian cancer) and specificity (ability to differentiate ovarian cancer from other conditions that cause abnormal test results).
Nevertheless, periodic surveillance is often recommended for women with a BRCA mutation who do not undergo prophylactic (preventive) surgery to remove the ovaries (see below). Screening for these women involves a combination of pelvic examination, vaginal ultrasound, and measurement of blood levels of CA 125 (a tumor marker used to determine the effectiveness of treatment in women with ovarian cancer that may also be useful in detecting ovarian cancer in women with no history of this cancer). The optimal frequency for screening has not been determined, although most centers recommend considering ovarian cancer screening every 6 to 12 months beginning between ages 25 and 35.
Family history of ovarian cancer — Women with a family history of ovarian cancer but who do not have a BRCA mutation should discuss their individual risk factors (age, number of children, and history of oral contraceptive pill use) with a healthcare provider. A woman is said to have a family history if she has one first degree relative (eg, mother, sister) or two second-degree relatives (eg, grandmother, aunt) with ovarian cancer.
Screening for ovarian cancer in this group has not proven to prevent death related to ovarian cancer. In addition, there are potential risks of screening, including the need for surgery if screening is positive. However, selected postmenopausal women with a family history of ovarian cancer may benefit from screening. An optimal screening strategy for this group has not yet been defined; one screening approach includes an annual CA 125 blood test; transvaginal ultrasound is recommended if the CA 125 level is above 30 U/mL.
Trials are currently underway to better identify the risks and benefits of screening low and high-risk women, and also to determine the most accurate combination of screening tests.
Prophylactic (preventive) surgery — As an alternative to undergoing frequent screening, some high-risk women consider prophylactic surgery to reduce their risk of developing a cancer. Prospective studies of women who undergo surgical removal of both breasts (termed a prophylactic bilateral mastectomy) show at least 90 percent reduction in the risk of breast cancer for high-risk women, including those with BRCA mutations [6,7].
Surgical removal of the ovaries and fallopian tubes (termed a prophylactic bilateral salpingo-oophorectomy, or BSO) has been shown to be protective against ovarian cancer (approximately 85 to 95 percent reduction) and breast cancer (approximately 40 to 50 percent reduction for premenopausal women) in carriers of BRCA mutations [8,9]. The benefits of BSO are greatest in women undergoing the procedure before menopause, particularly before age 40, after childbearing has been completed. Due to the lack of effective tests for ovarian cancer screening (see "Ovarian cancer screening" above), it is recommended that BRCA1 and BRCA2 carriers undergo prophylactic BSO by age 35, or once childbearing is completed.
Despite these benefits, only a small minority of women who are mutation carriers pursue prophylactic surgery, particularly mastectomy. However, studies of women who have undergone prophylactic mastectomy have found that the large majority reported satisfaction [15]. Prophylactic BSO is generally more accepted, perhaps because of the limited effectiveness of screening for ovarian cancer and because it reduces risk of both ovarian and breast cancer.
Prophylactic surgery may have psychological benefits by reducing a woman's concern that she'll develop cancer, but there are also risks that her quality of life may be negatively affected by surgery. It is important to discuss the medical, psychological, and emotional impact of prophylactic surgery before considering such surgery.
Medications to reduce the risk of cancer — The drugs tamoxifen and raloxifene may prevent the development of breast cancer (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Oral contraceptives have also been studied for use in preventing breast cancer.
Tamoxifen — Studies evaluating the benefit of tamoxifen in BRCA mutation carriers are limited. Early reports suggest that at least in women who have breast cancer and a BRCA mutation, tamoxifen can reduce the risk of getting a second breast cancer in the opposite breast by about 40 to 50 percent [10]. However, whether this improves survival, and whether tamoxifen is beneficial for mutation carriers who do not have breast cancer are unknown.
There are risks of taking tamoxifen. It increases the risk of the following, particularly in patients over the age of 50 (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"): Cancer of the lining of the uterus (endometrial cancer and sarcoma) Stroke Blood clots within deep veins, usually in the legs (deep vein thrombosis) Blood clots in the lungs (pulmonary embolism)
Raloxifene, in contrast to tamoxifen, is not associated with many of the most serious side effects seen with tamoxifen. However, it has not been studied yet in women with BRCA mutations, and its benefits in this group are unknown.
Oral contraceptives — Use of oral contraceptives (birth control pills) is associated with a decreased risk of ovarian cancer in the general population. The situation in women with inherited BRCA mutation is less clear. At least one study suggests that oral contraceptives decrease ovarian cancer risk in BRCA mutation carriers [11], but other studies have not confirmed this finding. In addition, there is concern that oral contraceptives may increase the risk of breast cancer, particularly in BRCA1 mutation carriers. More information about oral contraceptives is available in a separate topic review. (See "Patient information: Hormonal methods of birth control").
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 Cancer Institute
(www.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The National Comprehensive Cancer Network (NCCN)
Includes physician guidelines for hereditary breast and/or ovarian cancer
(www.nccn.org)
The American Cancer Society
Includes a guide to the causes of breast cancer with a discussion of BRCA genes
(www.cancer.org)
The Susan G. Komen Breast Cancer Foundation
(www.komen.org)
National Ovarian Cancer Coalition
(www.ovarian.org/)
Facing Our Risk of Cancer Empowered (FORCE)
(www.facingourrisk.com)
[1-4,6-14]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. BRCAPRO is a component of the CancerGene program, available online at www3.utsouthwestern.edu/cancergene/ (Accessed April 24, 2007).
2. www.cancer.gov/search/genetics_services/ (accessed April 24, 2007).
3. www.genome.gov/PolicyEthics/ (acceessed April 24, 2007).
4. www.facingourrisk.org (accessed April 24, 2007).
5. Saslow, D, Boetes, C, Burke, W, et al. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007; 57:75.
6. Rebbeck, TR, Friebel, T, Lynch, HT, et al. Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. J Clin Oncol 2004; 22:1055.
7. Hartmann, LC, Schaid, DJ, Woods, JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer [see comments]. N Engl J Med 1999; 340:77.
8. Rebbeck, TR, Lynch, HT, Neuhausen, SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346:1616.
9. Kauff, ND, Satagopan, JM, Robson, ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002; 346:1609.
10. Metcalfe, K, Lynch, HT, Ghadirian, P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22:2328.
11. Narod, SA, Risch, H, Moslehi, R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998; 339:424.
12. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005; 143:355.
13. Hampel, H, Sweet, K, Westman, JA, et al. Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J Med Genet 2004; 41:81.
14. Segal, J, Esplen, MJ, Toner, B, et al. An investigation of the disclosure process and support needs of BRCA1 and BRCA2 carriers. Am J Med Genet 2004; 125A:267.
15. Geiger, AM, Nekhlyudov, L, Herrinton, LJ, et al. Quality of life after bilateral prophylactic mastectomy. Ann Surg Oncol 2007; 14:686.
Other women with a personal history of breast cancer, particularly if it was diagnosed at a young age, may worry that if they have inherited a tendency to develop breast and/or ovarian cancer, it may be passed on to their children.
Inherited mutations in two genes (known as BRCA1 and BRCA2) have been shown to increase the risk of both breast cancer and ovarian cancer. Genetic testing is available that may identify individuals who have inherited an altered form of one of these genes that increases the risk of breast and/or ovarian cancer. Patients who test positive can consider intensified screening or interventions to decrease the risk of cancer (medications or surgical removal of the breasts, ovaries, or both).
However, genetic testing for BRCA mutations is imperfect. Most women with a family history of breast cancer have not inherited one of these two abnormal genes, and not all women who have inherited one of these genes will develop cancer. Furthermore, the results of BRCA testing may be confusing, and do not always lead to a clear action plan. Genetic testing for BRCA mutations can create emotional turmoil and family discord, and may have an impact on future medical care and insurability. Thus, it is important for the patient, her healthcare provider, and family members to carefully consider whether to undergo such testing.
This topic review will focus on which women should consider genetic testing for the presence of BRCA mutations, issues to consider before undergoing testing, and the available options for women who are found to carry one of these mutations.
Genetic testing is not an emergency procedure. Taking time to understand the complexities, and discussing questions with health-care professionals and family members can help to clarify expectations from testing and anticipate future issues.
GENETIC TESTING GOALS — Genetic testing for breast and/or ovarian cancer analyzes the composition of the BRCA genes to look for alterations (mutations) associated with breast and/or ovarian cancer.
How do genes relate to cancer? — A person's visible characteristics (such as hair and eye color) as well as other invisible properties (including predisposition to cancer and other diseases), are determined by his or her genetic "blueprint", which is inherited from both parents as 23 pairs of chromosomes. Each chromosome is made up of a long strand of DNA. Discrete segments or sections of the DNA (called genes) contain the information that is needed to construct specific proteins that carry out the specific function of the individual cells that make up the body. There are approximately 30,000 human genes distributed among the 23 pairs of human chromosomes.
Most of the time, genes function properly and the body develops and performs normally. However, when a gene is altered (often by a mutation or change in the chemical structure of the gene), it may not provide the right signals to the body's cells to carry out their normal functions. If the affected gene is normally involved in the regulation of cell growth, a mutated gene may result in signals that allow uncontrolled cell growth. This process of uncontrolled cell growth causes tumors such as breast cancer to grow unchecked within the body.
An inherited mutation (ie, one that is passed from parent to child, and is present in all cells at the time the child is born) is called a germline mutation. In contrast, a noninherited mutation (ie, one that comes about during a person's lifetime) is called an acquired mutation. Acquired mutations can be caused by exposure to environmental agents such as radiation, chemicals (including those found in tobacco smoke), or viruses; they may also happen spontaneously. Most human cancers are thought to be caused by acquired mutations.
Most breast cancers (at least 90 percent) are not related to inherited (germline) mutations. However, for those 5 to 10 percent that are due to germline mutations, BRCA1 and BRCA2 mutations are thought to account for the majority. These genes are called tumor suppressor genes, meaning that they normally function to keep the growth of the body's cells under control. When one of these genes becomes mutated, cell growth becomes unregulated, paving the way for the development of a cancer. Most scientists believe that a cancer develops only if additional genetic mutations are acquired.
Other genes — Besides BRCA1 and BRCA2, a few other genes have been identified that are associated with breast and/or ovarian cancer, but in general, these involve rare syndromes that are related to other medical conditions and cancer types. There are also likely other, not-yet-identified, genes that are involved in inherited breast and/or ovarian cancer. This topic review will focus only on the BRCA genes.
WHO SHOULD CONSIDER GENETIC TESTING? — Genetic testing should not be done in all women with a family history of breast and/or ovarian cancer since BRCA1 and BRCA2 mutations are rare. Determining which women should consider genetic testing involves examination of an individual's personal and family history of breast cancer and/or ovarian cancer.
BRCA mutations occur in approximately 0.1 percent of individuals (1 in 1000 people). However, some ethnic groups have a higher chance of inheriting one of these mutations. For example, about 2 percent of women of Ashkenazi Jewish (Eastern European) descent carry a BRCA1 or BRCA2 mutation, and between 12 and 30 percent of breast cancers in this group are thought to be caused by mutations in the BRCA1 or BRCA2 genes. These statistics do not consider a family history of breast and/or ovarian cancer.
Because germline mutations are rare, and testing for them can produce indeterminate results, testing is usually offered to women who are at a high risk of having a BRCA mutation. Tools are available (such as a computer program called BRCAPRO [1]) to estimate the likelihood of a woman having a BRCA mutation based on her individual and personal history. Typically, a woman's health care provider or a genetics counselor will ask a set of questions about a woman's personal and family history and plug the answers into this risk assessment tool. The program then calculates an estimate of the chances of finding a BRCA mutation based upon a number of risk assessment tools. Guidelines from national organizations suggest that if the estimated chance of inheriting one of these mutations is greater than 10 percent (one in ten), genetic testing may be appropriate.
However, current recommendations are moving away from numerical cut-off values for determining when genetic testing should be offered. Instead, many organizations advocate using more details of an individual's and family's history as a screening tool to identify women who should be considered for BRCA testing.
Family history patterns — Doctors and patients should be aware of family history patterns that are associated with a higher risk of a BRCA mutation. These include: Multiple relatives affected with breast and/or ovarian cancer, particularly if they were diagnosed at an early age (less than 50 years old) A relative with more than one cancer, such as breast cancer involving both breasts or breast and ovarian cancer Evidence that multiple generations of a family are affected.
Women who develop breast cancer before the age of 50 are more likely to have a mutation than those who develop breast cancer at an older age. If a young woman develops breast cancer and also has a family history of breast and/or ovarian cancer, her chance of carrying a mutation increases dramatically. Family history on the father's side is as important as maternal history.
When there is a strong family history of breast and/or ovarian cancer, BRCA testing should be done on the relative who has the cancer whenever possible. If a mutation is not found, it is usually not helpful to test unaffected relatives. If a relative with breast cancer tests positive for a BRCA mutation, genetic testing should be considered for all of her at-risk adult relatives (male and female).
TESTING PROCEDURE
Pre-test counseling — Genetic testing involves taking a sample of blood and sending it to a lab for testing. However, a woman must consider a number of factors before deciding to undergo genetic testing. These include medical, emotional, practical, and financial factors that can profoundly affect a woman and her family. Women who are considering genetic testing should discuss these issues with a certified genetic counselor, if possible, to understand what is involved in the process of genetic testing. A list of certified genetics counselors and their phone numbers is available through the National Cancer Institute [2].
An example of a consent form is presented in table 1 (show table 1A-1D), and briefly discussed below.
Emotional effects for patient — Although anxiety may cause some high-risk individuals to refuse genetic testing, the available data suggest that there are no major adverse psychological effects of learning the results of BRCA testing. In fact, data from families with hereditary cancer and from individuals who underwent genetic testing in clinic settings suggest less distress in members of high-risk families who test negative for a familial mutation.
While it is normal for individuals who test positive (mutation carriers) to experience some level of distress, anxiety, or sadness, most studies suggest that these individuals do not suffer serious psychological effects or significantly increased distress levels. For many individuals, learning about positive test results can also produce feelings of relief, as risk information is clarified and a plan for managing that risk can be put into place. Women who have less significant family histories and who do not expect to receive positive results may be more vulnerable to psychological problems or high levels of distress after BRCA testing. In families that have a known BRCA mutation, it is not unusual for women who test negative to experience "survivor's guilt" for being spared a burden that other relatives have to endure.
Effects on family members — A discussion of the implications of the test results for family members is an important component of counseling. This includes identifying at-risk family members and encouraging patients to share results with their relatives.
The decision to share test results with relatives and the ramifications of that decision can cause significant emotional strain and family discord. The role of information "gatekeeper" may be overwhelming for some women, particularly as they try to attend to their own needs for emotional support. Nevertheless, studies have found that most individuals, including carriers and non-carriers, opt to share their results with at-risk relatives. For many individuals who seek testing, gaining information for family members is one of the most important benefits of testing.
Costs and insurance coverage — Because the BRCA genes are large and include hundreds of different mutations, testing is expensive. Commercial charges by Myriad Genetics Laboratories® (which are subject to change) are as follows: Full BRCA1/2 testing, which includes testing for five large rearrangements in BRCA1 and for very high risk families, rearrangement testing in BRCA1 and BRCA2 — $3120 Once a mutation is identified in an affected individual, analysis for the specific mutation in relatives costs $385 Analysis of the three specific mutations most commonly seen in Ashkenazi Jewish individuals is $460
A list of testing laboratories is available through the Gene Tests website, at www.genetests.org (click on "Laboratory Directory"). However, full sequencing is provided in the United States by only one commercial laboratory, Myriad Genetic Laboratories®. Genetic testing for BRCA1 and BRCA2 is very expensive, but in the United States, most health insurance companies will cover 80 percent or more of the costs. In many instances, a letter of medical necessity is required from a physician or genetic counselor to demonstrate the potential impact of a positive test result on future care (eg, whether a positive result will be used to intensify screening efforts or recommend surgery). Many people are concerned about the possibility of health insurance discrimination if they have a positive result from a genetic test. This phenomenon has been difficult to document. Two types of insurance may be affected for patients who test positive: the person's health insurance and their life insurance.
The 1996 Health Insurance Portability and Accountability Act (HIPAA) contains provisions to protect individuals with group insurance from having their individual health insurance premiums raised or canceled because of a preexisting condition, including a genetic test result. Some state laws also provide protection. However, there are loopholes that do not cover people with individual (private) insurance and those applying for life insurance. Several websites are available that provide additional information on this subject [3,4]. The effect of a positive genetic test on the ability to obtain life insurance is less clear. Presently there are no federal laws addressing this issue.
Options for treatment if a mutation is identified — Before a genetic test is done, it is important that the woman understand her options for treatment (see "Options after testing positive" below).
Post-test counseling — It is a good idea to schedule an in-person meeting with a genetics counselor or physician to receive the genetic testing results. During this meeting, test results will be explained. This is an excellent time to bring up any questions related to the testing technique or reliability of results.
During the post-test counseling session, patients should review the possible implications of test results on family members. Patients are encouraged to share their results with family members.
INTERPRETING THE RESULTS — Interpretation of test results is not always clear cut. A negative test does not mean that a woman will never develop cancer; nor does a positive test mean that she will definitely develop cancer.
The easiest tests to interpret are those done after a mutation has already been identified in one or more close relatives who have breast and/or ovarian cancer. A positive result occurs when an individual tests positive for the same mutation as their relatives. A negative result occurs when an individual tests negative for a mutation that has already been identified in their family.
If an affected high-risk individual is the first to be tested in a specific family, results may be less clear. There are a number of possible results: A mutation could be present in BRCA1 or BRCA2 but was not detected by available methods A mutation in another risk-conferring gene that is rare and/or not yet identified could be present The individual being tested could have developed a sporadic (noninherited) rather than hereditary cancer. Another possibility is that a BRCA1 or BRCA2 alteration may be identified that is considered to be a "variant of uncertain significance." This means that it could possibly be a newly identified deleterious mutation or it could simply be a normal change in the gene. Such changes appear to be more common in certain ethnic groups, such as African-Americans. Further research will clarify the significance of many of these changes.
OPTIONS AFTER TESTING POSITIVE — Usually, women who test positive for a BRCA mutation are referred to specialists who can review their options. Several alternatives are available for women who are at increased risk for breast and ovarian cancer: increased surveillance (screening) for breast and ovarian cancer, preventive surgery, and/or the use of medications to reduce the risk of cancer (called chemoprevention). Cancer risk might best be decreased through a combination of some or all of these methods (show table 2). Women considering genetic testing should discuss the table with their healthcare provider.
Intensified breast cancer screening — Women who have inherited BRCA1 or BRCA2 mutations are recommended to increase the level and frequency of screening strategies as follows: Monthly breast self-examination (BSE) beginning at age 18; women should be specifically instructed on how to perform BSE) Clinical breast examination two to four times annually beginning at age 25 Annual mammography beginning at age 25; in some women, mammography may be recommended every 6 months Annual breast MRI to take place approximately 6 months after the annual mammogram. Magnetic resonance imaging (MRI) uses a strong magnet rather than x-rays or radiation to create a detailed image of a part of the body. Breast MRI appears to be more sensitive than screening mammogram for detecting early breast cancers in high-risk women, and several experts groups (including the National Comprehensive Cancer Network and the American Cancer Society) now recommend annual breast MRI for these women.
However, there are insufficient data to recommend breast MRI instead of screening mammography in any group of women. One reason is that MRI does not appear to be as sensitive for diagnosing conditions such as ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer.
Despite these recommendations by several expert groups, studies do not definitively prove that intensive screening improves cancer outcomes in women who inherit BRCA mutations. A major problem is that many of the screening tests are not sensitive enough to pick up early cancers at a time when they are most likely to be cured.
Ovarian cancer screening
High risk women — Women who have inherited a BRCA mutation have an increased risk of developing ovarian cancer and may benefit from tests to detect it at an early stage. However, unlike screening for breast cancer, screening tests for ovarian cancer are not very accurate in detecting disease. These tests have suboptimal sensitivity (ability to detect early ovarian cancer) and specificity (ability to differentiate ovarian cancer from other conditions that cause abnormal test results).
Nevertheless, periodic surveillance is often recommended for women with a BRCA mutation who do not undergo prophylactic (preventive) surgery to remove the ovaries (see below). Screening for these women involves a combination of pelvic examination, vaginal ultrasound, and measurement of blood levels of CA 125 (a tumor marker used to determine the effectiveness of treatment in women with ovarian cancer that may also be useful in detecting ovarian cancer in women with no history of this cancer). The optimal frequency for screening has not been determined, although most centers recommend considering ovarian cancer screening every 6 to 12 months beginning between ages 25 and 35.
Family history of ovarian cancer — Women with a family history of ovarian cancer but who do not have a BRCA mutation should discuss their individual risk factors (age, number of children, and history of oral contraceptive pill use) with a healthcare provider. A woman is said to have a family history if she has one first degree relative (eg, mother, sister) or two second-degree relatives (eg, grandmother, aunt) with ovarian cancer.
Screening for ovarian cancer in this group has not proven to prevent death related to ovarian cancer. In addition, there are potential risks of screening, including the need for surgery if screening is positive. However, selected postmenopausal women with a family history of ovarian cancer may benefit from screening. An optimal screening strategy for this group has not yet been defined; one screening approach includes an annual CA 125 blood test; transvaginal ultrasound is recommended if the CA 125 level is above 30 U/mL.
Trials are currently underway to better identify the risks and benefits of screening low and high-risk women, and also to determine the most accurate combination of screening tests.
Prophylactic (preventive) surgery — As an alternative to undergoing frequent screening, some high-risk women consider prophylactic surgery to reduce their risk of developing a cancer. Prospective studies of women who undergo surgical removal of both breasts (termed a prophylactic bilateral mastectomy) show at least 90 percent reduction in the risk of breast cancer for high-risk women, including those with BRCA mutations [6,7].
Surgical removal of the ovaries and fallopian tubes (termed a prophylactic bilateral salpingo-oophorectomy, or BSO) has been shown to be protective against ovarian cancer (approximately 85 to 95 percent reduction) and breast cancer (approximately 40 to 50 percent reduction for premenopausal women) in carriers of BRCA mutations [8,9]. The benefits of BSO are greatest in women undergoing the procedure before menopause, particularly before age 40, after childbearing has been completed. Due to the lack of effective tests for ovarian cancer screening (see "Ovarian cancer screening" above), it is recommended that BRCA1 and BRCA2 carriers undergo prophylactic BSO by age 35, or once childbearing is completed.
Despite these benefits, only a small minority of women who are mutation carriers pursue prophylactic surgery, particularly mastectomy. However, studies of women who have undergone prophylactic mastectomy have found that the large majority reported satisfaction [15]. Prophylactic BSO is generally more accepted, perhaps because of the limited effectiveness of screening for ovarian cancer and because it reduces risk of both ovarian and breast cancer.
Prophylactic surgery may have psychological benefits by reducing a woman's concern that she'll develop cancer, but there are also risks that her quality of life may be negatively affected by surgery. It is important to discuss the medical, psychological, and emotional impact of prophylactic surgery before considering such surgery.
Medications to reduce the risk of cancer — The drugs tamoxifen and raloxifene may prevent the development of breast cancer (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Oral contraceptives have also been studied for use in preventing breast cancer.
Tamoxifen — Studies evaluating the benefit of tamoxifen in BRCA mutation carriers are limited. Early reports suggest that at least in women who have breast cancer and a BRCA mutation, tamoxifen can reduce the risk of getting a second breast cancer in the opposite breast by about 40 to 50 percent [10]. However, whether this improves survival, and whether tamoxifen is beneficial for mutation carriers who do not have breast cancer are unknown.
There are risks of taking tamoxifen. It increases the risk of the following, particularly in patients over the age of 50 (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"): Cancer of the lining of the uterus (endometrial cancer and sarcoma) Stroke Blood clots within deep veins, usually in the legs (deep vein thrombosis) Blood clots in the lungs (pulmonary embolism)
Raloxifene, in contrast to tamoxifen, is not associated with many of the most serious side effects seen with tamoxifen. However, it has not been studied yet in women with BRCA mutations, and its benefits in this group are unknown.
Oral contraceptives — Use of oral contraceptives (birth control pills) is associated with a decreased risk of ovarian cancer in the general population. The situation in women with inherited BRCA mutation is less clear. At least one study suggests that oral contraceptives decrease ovarian cancer risk in BRCA mutation carriers [11], but other studies have not confirmed this finding. In addition, there is concern that oral contraceptives may increase the risk of breast cancer, particularly in BRCA1 mutation carriers. More information about oral contraceptives is available in a separate topic review. (See "Patient information: Hormonal methods of birth control").
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 Cancer Institute
(www.nci.nih.gov/)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The National Comprehensive Cancer Network (NCCN)
Includes physician guidelines for hereditary breast and/or ovarian cancer
(www.nccn.org)
The American Cancer Society
Includes a guide to the causes of breast cancer with a discussion of BRCA genes
(www.cancer.org)
The Susan G. Komen Breast Cancer Foundation
(www.komen.org)
National Ovarian Cancer Coalition
(www.ovarian.org/)
Facing Our Risk of Cancer Empowered (FORCE)
(www.facingourrisk.com)
[1-4,6-14]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. BRCAPRO is a component of the CancerGene program, available online at www3.utsouthwestern.edu/cancergene/ (Accessed April 24, 2007).
2. www.cancer.gov/search/genetics_services/ (accessed April 24, 2007).
3. www.genome.gov/PolicyEthics/ (acceessed April 24, 2007).
4. www.facingourrisk.org (accessed April 24, 2007).
5. Saslow, D, Boetes, C, Burke, W, et al. American Cancer Society guidelines for breast cancer screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007; 57:75.
6. Rebbeck, TR, Friebel, T, Lynch, HT, et al. Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. J Clin Oncol 2004; 22:1055.
7. Hartmann, LC, Schaid, DJ, Woods, JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer [see comments]. N Engl J Med 1999; 340:77.
8. Rebbeck, TR, Lynch, HT, Neuhausen, SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346:1616.
9. Kauff, ND, Satagopan, JM, Robson, ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002; 346:1609.
10. Metcalfe, K, Lynch, HT, Ghadirian, P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22:2328.
11. Narod, SA, Risch, H, Moslehi, R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998; 339:424.
12. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med 2005; 143:355.
13. Hampel, H, Sweet, K, Westman, JA, et al. Referral for cancer genetics consultation: a review and compilation of risk assessment criteria. J Med Genet 2004; 41:81.
14. Segal, J, Esplen, MJ, Toner, B, et al. An investigation of the disclosure process and support needs of BRCA1 and BRCA2 carriers. Am J Med Genet 2004; 125A:267.
15. Geiger, AM, Nekhlyudov, L, Herrinton, LJ, et al. Quality of life after bilateral prophylactic mastectomy. Ann Surg Oncol 2007; 14:686.
Subscribe to:
Posts (Atom)