Kidney Cancer Specialists  Arie Belldegrun, MD Jean B. deKernion, MD Mark S. Litwin, MD, MPH Allan Pantuck, MD, MS, FACS Robert E. Reiter, MD Robert B. Smith, MD Ongoing Clinical Trials Kidney Cancer - Ajuvant Trial – NON-METASTATIC DISEASE Kidney Cancer - Metastatic RCC – PREVIOUSLY UNTREATED Kidney Cancer - A phase III, Randomized Study Kidney Cancer - Metastatic RCC – PREVIOUSLY TREATED Kidney Cancer - A Phase II Study of M200 Kidney Cancer - Wilex cG250 - A Randomized Phase III Study for patients with Kidney Cancer Related Research Projects Research Studies in Urologic Oncology Dendritic Cell Therapy The UCLA Integrated Staging System (UISS)

General Information

Early diagnosis of kidney cancer is important. As with most types of cancer, the earlier the tumor is discovered, the better a patient's chances for survival. Tumors discovered at an early stage often respond well to treatment. Survival rates in such cases are high. Tumors that have grown large or spread (metastasized) through the bloodstream or lymphatic system to other parts of the body are more difficult to treat and present an increased risk for mortality.

Incidence and Prevalence
According to the National Cancer Institute, the highest incidence of kidney cancer occurs in the United States, Canada, Northern Europe, Australia, and New Zealand. The lowest incidence is found in Thailand, China, and the Philippines.

In the United States, kidney cancer accounts for approximately 3% of all adult cancers. According to the American Cancer Society, about 32,000 new cases are diagnosed and about 12,000 people die from the disease annually. Kidney cancer occurs most often in people between the ages of 50 and 70, and affects men almost twice as often as women.

Smokers develop renal cell carcinoma about twice as often as nonsmokers and develop cancer of the renal pelvis about 4 times as often. Not smoking is the most effective way to prevent kidney cancer and it is estimated that the elimination of smoking would reduce the rate of renal pelvis cancer by one-half and the rate of renal cell carcinoma by one-third.

Wilms' tumor accounts for about 6% of childhood cancers and is the most common type of kidney cancer in children. Incidence of Wilms' tumor is higher in girls younger than the age of 5 and in African Americans.

The Kidneys
The kidneys are an essential part of the body's urinary system. Each kidney is composed of about one million microscopic "filtering packets" called glomeruli. The glomeruli remove uremic waste products from the blood. Each glomerulus connects to a long tube, called the tubule. Urine made by the glomerulus moves down the tubule. Together, the glomerulus and the tubule form a unit called a nephron. Each nephron connects to progressively larger tubular branches, until it reaches a large collection area called the calyx. The calices form the funnel-shaped portion of the upper ureter (renal pelvis). Urine moves from the renal pelvis to the ureters, the large tubes that connect the kidney to the bladder.

The kidneys produce three important hormones: erythropoietin (EPO), which triggers the production of red blood cells in bones; renin, which regulates blood pressure; and vitamin D, which helps regulate the body's metabolism of calcium necessary for healthy bones.

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Risk Factors

There are several risk factors associated with the renal cell carcinoma.

Smoking
There is strong evidence that cigarette, pipe, and cigar smoking doubles a person's risk for developing RCC. Researchers estimate that 25% to 30% of all renal cell cancers are directly attributable to smoking.

Overuse of Painkillers
Medications containing phenacetin, which were once commonly used over-the-counter painkillers, have been linked to RCC, typically in patients who used them to excess. While these drugs were removed from U.S. markets more than 20 years ago, older Americans who used them may be at risk for RCC.

Chemical Exposure
Studies have shown that exposure to certain substances increases the risk of RCC. Asbestos, once commonly used as an insulating material, and cadmium, formerly an ingredient in certain colored inks and paints, have been linked to kidney cancer. People who may have come into contact with these substances, such as construction and shipyard workers, painters and printers, may have an increased risk for RCC.

Genetics
People with a family history of kidney cancer are at increased risk for RCC. It is suspected that inherited genetic mutations may be the cause, perhaps triggered by damage to the DNA that forms genes; cigarette smoke, for example, is known to contain chemicals that can damage the genes of kidney cells.

Other genetic mutations may cause two rare forms of kidney cancer. Von Hippel-Lindau syndrome is a disease that causes multiple tumors of the brain, spine, eyes, adrenal glands, pancreas, inner ear, testicles, and kidneys. Tuberous sclerosis is a disease characterized by small tumors of the blood vessels, which result in numerous bumps on the skin, mental retardation, seizures, cysts in the kidneys, liver, and pancreas and RCC.

Other Risk Factors

• Age - RCC occurs most frequently in adults 50 - 70 years old.
• Diet and weight - High-fat diet and obesity may increase the risk for RCC.
• Extended dialysis - Patients treated with long-term dialysis may develop cysts in their kidneys, a risk factor for RCC.
• Estrogen - Test animals have developed RCC when given estrogens.
• Gender - Men are twice as likely as women to develop RCC.

The primary symptoms of RCC include the following:

• Abdominal mass or lump
• Blood in the urine (hematuria)
• Fever
• High blood pressure (hypertension)
• Pain in the side (flank) or lower back not associated with injury
• Persistent fatigue
• Rapid, unexplained weight loss
• Swelling (edema) in the legs and ankles

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Diagnosis Diagnosis

If the physician suspects RCC, a series of examinations, procedures, and laboratory tests are performed to confirm the diagnosis. A thorough physical examination is performed to assess the patient's health and obtain information about symptoms and a medical history is taken to determine if there are risk factors for RCC.

Imaging Tests
One or more imaging tests are performed to obtain pictures of the kidney(s) and locate abnormalities. Some imaging tests require the injection of a special "tracer" material (dye or low-level radioactive isotope) into the patient's bloodstream.

Computed tomography (CT scan)
CT scan is a type of x-ray that produces a series of cross-sectional, three-dimensional images of internal organs and glands. It can detect tumors and, in some cases, lymph nodes enlarged by cancer.

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Magnetic resonance imaging (MRI scan)
An MRI scan uses large magnets to project magnetic waves through the body and create computer-generated, cross-sectional images of internal organs.

Ultrasound
Ultrasound uses sound waves projected into the body to produce an image of internal organs, structures, and tumors. In this procedure, a gel is applied to the patient's pelvic and kidney areas, and a small device that emits ultrasonic pulses is slowly passed over the area. The sonic image produced is viewed on a monitor.

Intravenous pyelogram (IVP)
An intravenous pyelogram (IVP) involves injecting a dye containing iodine through a vein in the arm into the bloodstream. The dye eventually collects in the urinary system, where it improves the contrast for x-rays and produces a well-defined image of the kidneys, ureters, and bladder. By showing up as white on the dark x-ray film, the IVP can detect tumors or damage caused by a tumor in the kidney.

In some cases, the physician may request an arteriogram or venacavagram (IVP of the blood vessels that supply the kidneys) to look for tumors in the connecting arteries and veins.

Chest x-ray
A standard chest x-ray may be used to detect RCC that has has spread (metastasized) to the lungs or bones in the chest.

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Bone scan
This nuclear imaging procedure is used to detect the spread (metastasis) of cancer to bones, when aggressive tumors and metastasis are suspected. In a bone scan, a small amount of low-level radioactive material is injected into a vein in the arm. This material discloses metastatic cancer, as well as some noncancerous diseases, in bones.

Laboratory tests
One or more laboratory tests are performed to confirm the presence of RCC.

Urinalysis
More than half of all patients with RCC have blood in the urine (hematuria). Often this blood is present in small amounts or diffused in the urine so that it cannot be seen with the naked eye (called microscopic hematuria). To detect hematuria, a chemical test of the urine is performed. On occasion, cells found in the urine are examined under a microscope for abnormalities. This procedure is called urine cytology.

Blood tests
Another laboratory procedure typically used in the diagnosis of RCC involves microscopic examination and/or chemical analysis of the patient's blood. These tests screen for the following conditions which may indicate the presence of cancer:

• Anemia (too few red blood cells; caused by internal bleeding, a common cancer symptom)
• Polycythemia (too many red blood cells; sometimes caused by cancerous tumors in the kidney that trigger the release of erythropoitin [EPO], a hormone that increases red blood cell production in bone marrow)
• Hypercalcemia (high blood calcium levels) and elevated liver enzymes

Cystoscopy
Blood in the urine can result from other health problems, such as kidney stones or traumatic kidney injury, so the doctor may order a cystoscopy to determine precisely where the internal bleeding is occurring. In cystoscopy, a long, thin, rigid or flexible optical scope is inserted through the urethra and into the bladder. The practitioner then makes a visual examination of the urethra, bladder, and kidneys to locate the site of bleeding.

Fine needle aspiration
RCC tumors are made up of cancerous (malignant) cells that grow into a mass. If a tumor is found through imaging or other procedures, a cell sample may be taken for microscopic examination.

Physicians usually avoid performing needle biopsies of suspected kidney tumors because of the risk for bleeding or other complications. Some tumors contain a fluid-filled cyst. A small amount of this fluid can be drawn out of the cyst for examination by a pathologist, who will look for and identify the cancer cells. This can help the physician determine an appropriate treatment plan. While no longer common, a similar technique can be used to collect a sample of solid tissue from a noncystic tumor.

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Pathology
Cells that make up RCC tumors fall into four categories based on their appearance under microscopic examination:

• Clear cell
• Granular cell
• Mixed clear and granular
• Sarcomatoid or spindle type

Under a microscope, clear cell cancers are the least abnormal. They are round or polygon-shaped and contain an abundance of fat and sugar. The tumors they produce are yellow to orange in color. Clear cell cancers are thought to be the least likely to spread (aggressive) and usually respond more favorably to treatment.

Few tumors contain only clear cells, however. Darker granular cells usually are present to some degree. These have a larger, darker nucleus and are full of tiny pink granules called mitochondria. The tumors they produce tend to be gray to white in color. Mitochondria are small, oval bodies that provide energy for cell growth. Their presence indicates a more aggressive form of cancer.

Tumors that contain both clear and granular cells are considered mixed. This is the most common form of RCC and indicates the most aggressive form of kidney cancer.

Mixed tumors that contain spindle shaped, sarcomatoid cells have the least favorable prognosis. Although tumors composed exclusively of spindle cells are uncommon, the presence of sarcomatoid cells indicates a form of cancer that grows and spreads quickly.

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The grade of a cancer cell is an assessment of its appearance compared to that of a normal, healthy cell. Grading is done on a scale of 1 to 4: Grade 1 RCC cells differ little from normal kidney cells, typically spread slowly, and have a good prognosis for treatment. Grade 4 RCC cells look extremely different and indicate an aggressive cancer with poor prognosis.

Staging

Although grading and the identification of cancer cell types help determine a patient's prognosis, most doctors believe that the cancer's stage is a better indicator of a patient's survivability.

Staging allows a physician to gauge the size and location of tumors by using information gathered from imaging studies such as CT scans and MRIs, and from pathology tests and physical examinations.

Staging factors that influence a patient's prognosis are:

• Spread to tissues surrounding the kidney
• Spread to contiguous organs
• Spread to nearby lymph nodes (the small, bean-shaped structures found throughout the body that produce and store infection-fighting cells)
• Distant metastasis

There are two staging systems for RCC, Robson and TNM.

The Robson system classifies tumors as stages.

The TNM (tumor-node-metastasis) system uses stages generally similar to those of the Robson system. This staging system is becoming more widely accepted because it provides a more detailed description of the tumor(s).

The TNM system stages RCC tumors at four intervals:

The TNM system also uses alphanumeric subcategories to define areas and degrees of invasion. These are as follows:

Primary tumor (T); all sizes measured in greatest dimension:

Regional lymph nodes (N):

Distant metastasis (M):

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Treatment

Once a diagnosis of renal cell cancer has been confirmed and the disease's stage determined, physician and patient decide on a treatment plan. Factors that are considered include the patient's age and overall health and the extent to which the cancer has spread. For example, a patient with one healthy, functioning kidney and one afflicted with an aggressive Stage 2 RCC is a more likely candidate for radical surgery than a patient with only one kidney and a less aggressive Stage 1 cancer.

It is important that the patient and physician make an informed decision together after considering all possible options, side effects, and outcomes. A confident, positive outlook can help the patient cope with the physical demands of surgery and/or therapy and can improve the chances for recovery.

A second opinion can provide additional information in the decision-making process and help the patient feel that he or she has made the right choice. Some insurance companies require a second opinion before they approve payment for treatment.

Treatment options include the following:

• Surgery (to remove cancerous tissue)
• Chemotherapy (using drugs to destroy cancer cells)
• Radiation therapy (using high-energy radiation to destroy cancer cells and shrink tumors)
• Hormone therapy (using hormones to prevent cancer cell growth)
• Biological or Immunotherapy (using compounds produced by the body's immune system, or laboratory-produced copies of them, to destroy cancer cells)

Two or more forms of treatment may be used in combination, such as surgery to remove a primary tumor followed by radiation treatment or chemotherapy to kill cancer cells that may remain in the body.

Another form of treatment, called gene therapy, is being explored by researchers who think inherited genetic mutations may cause many cases of RCC. Eventually, a process that uses normal genes to overcome or reverse the cancer-causing process may be developed.

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Surgery
Surgery usually is required to treat RCC. Without it, most patients' chances for survival are poor. Several surgical options are available to the patient and physician; which is most appropriate depends on the patient's condition and the cancer's stage.

Radical Nephrectomy
The most common form of surgery for RCC, radical nephrectomy involves removal of the entire kidney, often along with the attached adrenal gland, surrounding fatty tissues and nearby lymph nodes (regional lymphadenectomy), depending upon how far the cancer has spread.

Partial Nephrectomy
It may be possible to remove only the cancerous tissue and part of the kidney if the tumor is small and confined to the very top or bottom of the kidney. A partial nephrectomy may be the procedure of choice for patients with RCC in both kidneys and for those who have only one functioning kidney.

Arterial Embolization
This procedure usually is reserved for patients whose health does not permit surgery, such as those with heart or lung disease. In arterial embolization, a very small tube (catheter) is inserted through a blood vessel in the groin and passed up to the kidney. A small piece of gelatin sponge is then injected into the artery that supplies blood to the cancerous kidney. This cuts off the flow of blood to the kidney and the cancerous tumor, and both die. The kidney usually is surgically removed at a later date, if and when the patient's health permits.

Surgical Risks
Any form of invasive surgery carries certain risks. Patients contemplating kidney surgery should be advised of the possibility of experiencing complications, such as the following:

• Damage to blood vessels (aorta or vena cava)
• Damage to organs (spleen, pancreas, large or small bowel)
• Failure of the remaining kidney
• Hemorrhage (bleeding) during surgery (intraoperative) or after surgery (postoperative)
• Incisional hernia (bulging of the internal organs beneath the surgical incision, caused by imperfect healing or damage to the overlying muscles)
• Infection
• Pneumothorax (unwanted air in the chest cavity)

Postoperative Prognosis
Renal cell cancer is unpredictable. It is the second most common tumor to undergo spontaneous regression following removal of the primary lesion; this occurs about 0.5% of the time. Another unusual characteristic of RCC is the variability in the growth of the primary tumor.

Once metastasis occurs, prognosis depends on the extent of the spread and the interval between appearance of metastases and the removal of the kidney.

Overall, the 5-year survival rate for RCC -- all stages combined -- is about 40-45%.

Follow-up Care and Recurrent Kidney Cancer
Some patients who undergo surgery to remove a cancerous kidney or kidney tumors experience a recurrence of the disease. For this reason, patients usually undergo a regimen of follow-up examinations after surgery, typically at 3-month intervals for the first year. These examinations include a complete physical examination, chest x-ray, complete blood tests, and assessments of liver and kidney function.

If the disease recurs but remains confined to a few small areas, additional surgery may be recommended. Radiation, biological, or chemotherapy also may be used in addition to surgery (adjuvant treatment) or to relieve symptoms (palliative treatment).

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Nonsurgical Treatments

Chemotherapy
Chemotherapy uses chemical agents to destroy cancer cells throughout the body. Unfortunately, RCC has proven to be particularly resistant to chemotherapy. Research to develop more effective chemotherapy drugs to treat RCC is ongoing, however, and a number of them are currently being tested.

Radiation Therapy
Radiation therapy involves using high-energy x-rays to shrink tumors and destroy cancer cells. This treatment may be delivered as a focused beam that is projected into the body (called external therapy) or in the form of radioactive materials placed at the site of the cancer through thin plastic tubes (called brachytherapy).

Radiation therapy is used often as follow-up (adjuvant) treatment to destroy cancer cells that remain in the body after a radical or partial nephrectomy.

It also may be used as palliative therapy to lessen pain or bleeding in patients with inoperable or widespread metastatic RCC. In such cases, there is no expectation of cure; the object is simply to ease the dying patient's discomfort.

Radiation therapy alone has a relatively low success rate in treating RCC, and often produces unpleasant side effects:

• Diarrhea
• Fatigue
• Headaches and cognitive problems (if treating metastatic cancer of the brain)
• Lung and respiratory problems (if treating cancer that has spread to the lungs or bones in the chest)
• Nausea
• Skin irritations

Hormone Therapy
Agents such as estrogen, progesterone, and tamoxifen have been used with varying degrees of success to stop some types of cancer from growing. There is little evidence, however, that hormone therapy, either primary or adjuvant, is effective when used to treat RCC. Some recent studies show success rates of 5% to 10%. At best, it remains a subject for future research.

Biological Therapy
Over the last 10 years, there has been much interest in the use of biological agents, primarily interleukin and interferon, to boost, restore, or direct the patient's immune system to fight RCC in the same way it would fight an infection. There are data to suggest that these agents effectively treat this disease and can at times produce complete remissions. Both interleukin and interferon are approved by the FDA for treating metastatic RCC.

Chemobiological Therapy
Some recent studies suggest that combining biological therapy with chemotherapy (chemobiological) therapy produces significantly higher response rates than biological therapy alone, although the data need to be confirmed in a larger study.

The side effects of chemobiological therapy include, but are not limited to the follwing:

• Depression
• Fatigue
• Fever
• Fluid retention and associated weight gain
• Loss of appetite
• Nausea
• Renal and liver failure
• Risk of infection and bleeding
• Skin rash

Other Types of Kidney Cancer

Transitional Cell Carcinoma
About 6% to 7% of kidney cancers begin not in the kidney itself, but in the renal pelvis, the point where the kidney joins the tube that carries urine form the kidney to the bladder (ureter). These tumors are called transitional cell carcinomas and are made up of cancer cells different from those that characterize RCC. Research indicates these tumors are caused by cigarette smoking.

The symptoms of transitional cell carcinoma are quite similar to those of RCC, and include hematuria and back or flank pain.

If found early, these cancers have a 90% cure rate. Treatment usually involves surgical removal of the kidney, ureter, and portion of the bladder connecting to the ureter. Depending on the stage of the cancer, chemotherapy and radiation may be used as adjuvant treatments.

The prognosis for cure dec

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Kidney Cancer and UCLA

Over 32,000 people in the United States are diagnosed with kidney cancer each year. Although kidney cancer remains a challenging disease to treat, exciting new breakthroughs in diagnosing and treating kidney cancer are being reported regularly. At UCLA, we believe that new advances will translate into curative therapy for more and more patients. 

Many patients with kidney cancer can be helped with a combination of surgery and immune based therapies.  The current goals for treatment include achieving a complete cure, and minimizing the impact of both the cancer as well as the treatment on quality of life.  Towards these ends, cancer therapy is tailored for each patient.  At the UCLA Kidney Cancer Center, our extensive experience and our many cutting-edge research studies allow us to provide the full gamut of treatment options.  We offer standard therapies as well as minimally invasive options and new experimental treatments.

Standard Treatment Options

Radical Nephrectomy:

For patients who have kidney tumors that are confined to the kidney, removal of the kidney offers the best chance for a cure.  Classically, a radical nephrectomy involves surgical removal of the kidney, the surrounding fatty tissue and the adrenal gland.  More recently, the need for removing the adrenal gland, especially for lower pole tumors, has been questioned.  At UCLA, we make an effort to preserve the adrenal gland whenever possible.

Laparoscopic Nephrectomy:

A radical nephrectomy can be performed using a laparoscope.  Traditional radical nephrectomy involves making a large incision in the abdomen to perform the surgery and remove the kidney.  However, when the kidney is removed laparascopically, several quarter-sized opening are made in the abdomen.  A laparoscope attached to a camera and specialized surgical instruments are inserted into the openings.  The entire surgery is performed through the small openings as video images of the surgical field are projected onto a monitor.  This type of surgery is associated with less pain and a more rapid recovery than the traditional open approach.

Partial Nephrectomy:

For patients with smaller, localized tumors, it may not be necessary to remove the entire kidney.  By performing a partial nephrectomy, maximum kidney function is preserved.  In patients who already have marginal kidney function, a partial nephrectomy may allow them to avoid a life dependent on dialysis.  Patients with small tumors located away from the hilum and the primary blood vessels are candidates for this procedure.  At UCLA, we recommend partial nephrectomies for renal tumors whenever possible.  Patients with decreased kidney function as a result of high blood pressure, diabetes, previous kidney surgery or extensive history of kidney stones, are ideal candidates for this nephron-sparing procedure.

Bilateral Nephrectomy:

Patients with hereditary renal carcinoma, such a von Hippel Lindau disease, typically have multiple, low grade tumors in both kidneys.  For such patients, simple removal of the tumors may be the best option.  With this approach, the risk of leaving cancer cells behind is minimal since the tumors are low grade and less aggressive.  This approach also preserves as much of the normal kidney as possible, allowing the patient to either delay or avoid the need for dialysis.  Patients with multiple tumors require very careful follow-up and they often require multiple partial nephrectomies throughout their lifetime, as new tumors form or as smaller tumors enlarge and become amenable to surgical resection. 

Cryotherapy:

For some tumors that are small and located at the outer edge of the kidney, cryotherapy can be performed.  Cryotherapy involves freezing the tumor to kill the cancer cells while preserving the surrounding, normal kidney.  The procedure can be done laparoscopically or using a traditional, open approach.  During the surgery, ultrasound imaging is used to localize the tumor and define the margins for the freezing process.

Immunotherapy:

Kidney tumors can invade other organs in the abdomen, or it can spread to distant sites such as the lymph nodes, lung, bones, or brain.  For patients with kidney cancer that has spread outside the kidney (metastasized), immunotherapy is currently the standard of care.  If a patient’s overall health status permits, a nephrectomy is performed before administering immunotherapy.  Studies performed at UCLA and other medical centers have demonstrated that performing a nephrectomy to remove the primary tumor before administering immunotherapy improves survival when compared to giving immunotherapy without a nephrectomy.  The immunotherapy usually involves administering interleukin-2 or interferon. 

Interleukin-2, often referred to as IL-2, is a cytokine that is normally produced by white blood cells.  It has various stimulatory effects on the immune system.  Synthetically produced interleukin-2 is currently FDA approved for the treatment of advanced kidney cancer.  At most centers, IL-2 is administered at a “low dose” in an outpatient setting.  However, recent studies indicate that “high dose” IL-2 treatments may be more effective than the lower dose treatments.  However, the “high dose” treatments are associated with significant side effects that require considerable expertise to manage.  UCLA has a dedicated program for treating patients with “high dose” IL-2.  The Kidney Cancer Center at UCLA has extensive experience evaluating potential candidates for “high dose” IL-2, administering the treatment and managing any side-effects.

Gene therapy

New developments in our understanding of molecular biology and immunology have allowed us to develop innovative approaches to treating metastatic kidney cancer.  In ongoing studies at UCLA, we are exploring new vaccines against metastatic cancer cells.  The kidney tumor obtained at the time of surgery can be processed and used as a vaccine to stimulate the immune system against metastatic deposits.  The immune system has the potential to very specifically target tumor cells, minimizing toxic side effects.  These techniques can be used separately or in conjunction with methods to stimulate the immune system using cytokines.  Cytokines are protein signals released by white blood cells that modulate immune function.  These approaches represent examples of state of the art technology in genetic engineering, immunotherapy and gene therapy. 

The Patient Health Questionnaire will enable our Kidney Cancer Team to be familiar with your medical history. Upon completion, please FAX this form to the Kidney Cancer Program at 310-794-7787. If a FAX machine is not available to you, it is imperative that the form be brought with you COMPLETED upon your arrival for your appointment in Clark Urology. Questions pertaining to this form may be answered by your local physician (and/or) oncologist