Therapies for Advanced Kidney Cancer
Sometimes surgical treatment alone is not sufficient for kidney cancer. If you had metastatic disease (cancer that has spread to other organs) when you were diagnosed, or if you have developed metastatic cancer since your nephrectomy, your doctor will most likely recommend additional treatment. The most commonly used treatments for kidney cancer are various forms of “targeted therapies” or immunotherapy. Targeted therapies — so-called because they “target” cancer at the cellular level — have expanded the options for the treatment of kidney cancer. Other traditional, but less-often used, treatments include radiation therapy and chemotherapy. Several investigational therapies, including vaccine therapy, are also available.
If you are a patient experiencing side effects from any of the FDA-approved medications that follow, the Kidney Cancer Association’s Nurse Telephone Information Service may be able to answer questions and provide assistance: +1 503-215-7921.
One of the most exciting new developments in recent years has been the introduction of drugs that interfere with the growth of cancer cells at a molecular level. By focusing on specific molecular growth pathways, these drugs can interfere with cell growth, prevent cell replication, or disrupt the blood flow supply to the cell. Much research is under way worldwide and it is yielding new targeted therapies as well as providing information about how they work. As more is learned about pathways of cells, it is likely that even more new drugs and treatments will be introduced.
For malignant tumors to expand and metastasize, they must be able to form new blood vessels by a process called angiogenesis. Tumors overproduce “growth factors” that stimulate the development of new blood vessels to supply oxygen and nutrition. These include “vascular endothelial growth factor” (VEGF) and “platelet-derived growth factor” (PDGF). These growth factors activate certain tyrosine kinases, proteins inside cancer cells that are important in cell functions, including the development of new blood vessels. This allows tumors to grow and to metastasize to other parts of the body.
In 2005 and 2006, the U.S. Food and Drug Administration (FDA) approved the first new medications to treat kidney cancer in more than a decade: sorafenib tosylate and sunitinib malate. Both of these new drugs disrupt the angiogenesis process. Known as tyrosine kinase inhibitors, they interfere with the proteins inside cancer cells, thus interfering with certain cell functions. These drugs are also known as “multi-kinase inhibitors” because they target both the tumor cell and the tumor blood vessel structures. They work by interfering with reproduction of cancer cells as they attempt to grow and divide uncontrollably. They also have the advantage of being administered orally.
The goal of treatment with these newer medications is to slow the rate of growth of the cancer and, if possible, shrink the size of existing tumors. Some patients may experience a significant decrease in the amount of cancer in their body. Some patients may not experience shrinkage in the size of their tumors, but have long periods of “stable” disease. Your physician will discuss how your cancer is responding to treatment, and will have additional options to consider for treatment when necessary. It should be noted that some patients will not receive any benefit from a medication. In some cases, a medication that was effective in treating a patient’s cancer stops working and other treatment options must be considered.
Nexavar® (sorafenib tosylate) is a medication that targets the blood supply of a tumor, depriving it of the oxygen and nutrients it needs for growth. By blocking the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), Nexavar can interfere with the tumor cell’s ability to increase its blood supply. By blocking the Raf-kinase pathway, Nexavar can also interfere with tumor cell growth and proliferation. Clinical studies show that it can significantly slow the progression of tumors. In the Phase III trial which led to the FDA approval of Nexavar, the median time for tumor progression was doubled for patients taking Nexavar, compared with patients taking a placebo.
Sutent® (sunitinib malate) also deprives tumor cells of the blood and nutrients needed to grow by interfering with VEGF and PDGF signaling pathways. Sutent was approved by the FDA in 2006 for kidney cancer patients because of its ability to reduce the size of tumors. Clinical studies showed a favorable response rate in patients with metastatic kidney cancer whose tumors had progressed following immunotherapy.
Torisel® (temsirolimus) is another recently approved kidney cancer drug. It was designed to inhibit the mTOR (mammalian target of rapamycin) kinase, which is important in cell growth and cell survival. By blocking the mTOR pathway, Torisel can interfere with the tumor’s ability to multiply as well as reducing its ability to stimulate angiogenesis.
Afinitor® (everolimus), approved by the FDA in March 2009, is an orally administered mTOR inhibitor. Afinitor works by blocking a specific protein known as the mammalian target of rapamycin (mTOR) and acts as a multifunctional inhibitor of cell growth and proliferation, angiogenesis, and cell metabolism. The drug is intended for those patients with advanced renal cell cancer who have already tried a kinase inhibitor, such as Sutent or Nexavar.
Votrient® (pazopanib), the sixth drug to be approved for kidney cancer since 2005, is an oral medication that interferes with angiogenesis, the growth of new blood vessels needed for solid tumors to grow. It is a kinase inhibitor indicated for the treatment of patients with advanced renal cell carcinoma.
Inlyta® (axitinib), approved by the FDA in January 2012, is a prescription medicine used to treat advanced kidney cancer (advanced renal cell carcinoma or RCC) when one prior drug treatment for this disease has not worked.
An antibody is a protein produced by the body’s immune system that fights infections and foreign substances in the body. Monoclonal antibodies are genetically engineered antibodies that are identical copies of one another. They are used in various medical diagnostic tests and are being studied for possible use in the treatment of cancer. Monoclonal antibodies can be designed to attach to particular sites on a tumor and may be used to produce images for diagnostic purposes or to deliver anti-cancer drugs to the tumor with great specificity. The use of monoclonal antibodies in the treatment of metastatic kidney cancer is under active investigation.
Avastin® (Bevacizumab), FDA-approved for kidney cancer in August, 2009, is a biologic antibody designed to specifically bind to a protein called vascular endothelial growth factor (VEGF) that plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels, a process known as angiogenesis. Avastin is designed to interfere with the blood supply to a tumor by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. Avastin does not bind to receptors on normal or cancer cells. The tumor blood supply is thought to be critical to a tumorʼs ability to grow and spread in the body (metastasize).
Your body’s immune system is responsible for protecting you from viruses, bacteria, and cancer cells. Immunotherapy, sometimes called biologic therapy, is a form of treatment that boosts the body’s own immune defenses. Immunotherapy is considered one of the standard treatment options for kidney cancer patients with advanced metastatic disease.
Well-documented, but very rare, cases of spontaneous regressions in kidney cancer patients with metastatic disease suggest that the immune system can play an important role in the control and potential treatment of this disease.
The building blocks of immunotherapy are biologic response modifiers (BRMs). They are substances that enhance the body’s immune system and improve its ability to fight cancer. BRMs do their work by regulating the intensity and duration of immune responses. A BRM can be either a manmade drug or a natural substance produced by the body.
Several BRMs can boost the body’s natural immune defenses. The cytokines are an important family of BRMs that include Interleukin-2 (IL-2) and Interferons. Used either alone or in combination, they have represented the standard in the treatment of kidney cancer.
Interleukin-2 is a biologic response modifier (BRM) available for the treatment of advanced kidney cancer. It stimulates the growth of two types of white blood cells: T cells and “natural killer” (NK) cells. T cells are very important in your body’s fight against cancer because they recognize cancer cells and set off an alarm to the body. The NK cells respond to this alarm and are transformed into lymphokine-activated killer (LAK) cells, which are capable of destroying cancer cells.
Proleukin® (interleukin-2) was approved by the FDA in 1992 for the treatment of metastatic renal cell carcinoma. A genetically engineered product, recombinant IL-2, is available for use in various therapeutic regimens. Several different routes of administration may be used: IV bolus, subcutaneous (SC), and continuous IV infusion (CIV). These are further classified as high-dose (IV bolus) or low-dose (SC and CIV). The term “high-dose or IV bolus” refers to the relatively large dose of a drug given intravenously as a 15-minute infusion every 8 hours for a maximum of 14 infusions to hasten or magnify a therapeutic response. When administered in this fashion, patients are admitted overnight to the hospital for the duration of the treatment cycle to be closely monitored. Recent statistics on long-term survival in patients treated with high-dose IL-2 continue to demonstrate that this therapy is effective for selected patients with metastatic renal cell carcinoma who can tolerate these large doses.
These results confirm the premise that immunotherapy has curative potential in metastatic renal cell carcinoma. In some cases, IL-2 therapy produces what are known as “durable complete responses” (results lasting greater than 10 years) in a small percentage of treated patients and represented a significant milestone in the treatment of kidney cancer. Significant toxicities are associated with IL-2 treatment. Side effects include nausea, vomiting, hypotension, cardiac arrythmias, diarrhea, loss of appetite, gastrointestinal bleeding, rashes, disorientation, hallucinations, fever, and chills. Most of these side effects are completely reversible on discontinuation of drug administration, but they can be severe. It is imperative that the treating doctor be experienced in the use of IL-2 and ensures diligent clinical monitoring of the patient during treatment.
Interferons are widely used to treat kidney cancer, alone or in combination with other drugs. Interferon therapy is typically self-administered by injection under the skin several times per week. Interferons work by “interfering” with the life processes within the cancer cell, preventing its growth and making the cell more susceptible to attack by other elements of the immune system.
There are three major types of interferons — alfa, beta, and gamma — but interferon alfa has been most widely studied in the treatment of kidney cancer. Several interferon alfa products are available in the United States and have been used in the treatment of kidney cancer. INTRON* A, a product of Schering Corporation (Kenilworth, NJ), has been designated as interferon alfa-2b. Roferon*-A is manufactured by Roche Laboratories (Nutley, NJ) and has been designated as interferon alfa-2a. These drugs are very similar, and kidney cancer may be treated with either. Most insurance companies recognize the value of interferon alfa in treating kidney cancer and reimburse for this therapy.
In several dozen clinical trials, an overall response rate of about 13% has been achieved with interferon alfa.29 However, in patients with high performance status (i.e., lack of symptoms related to their disease), previous nephrectomy, and metastases predominantly in the lung, the major response rate (complete plus partial responses) with interferon alfa treatment is usually from 6 to 10%. It is also recognized that patients who receive interferon alpha, when compared with those who are treated with hormones or chemotherapy, have improved survival rates.
Response to interferon alfa is characterized by slow regression of tumors; the average time from start of treatment to objective response is three to four months.
The most common side effects of interferon therapy are flu-like in nature. They include fever, chills, muscle aches, headache, loss of appetite, and fatigue. Generally, these symptoms become less severe with continued therapy. Administering interferon in the evening and taking a nonprescription pain medication can help relieve these symptoms. However, other symptoms may appear with prolonged use of interferon, including weight loss, lower white blood cell counts, extra heartbeats, loss of interest in sex, mental confusion, and depression. If severe, side effects may require stopping the therapy. Fortunately, the side effects of interferon are not permanent. A dose of 5 to 20 million units of interferon alfa daily appears to have maximal efficacy and avoids the more serious toxicities associated with higher doses.
Though it is not considered a primary form of therapy, radiation can be used in the treatment of kidney cancer that has metastasized to the bone, brain or spine. It may be used to control symptoms – relief from pain, for example.
There are several different types of radiation therapy; all work on the same basic principle of using high-energy radiation to kill cancer cells or slow their rate of growth. Radiation therapy is a “localized” treatment, targeted as precisely as possible at a specific area or tumor. Radiation therapy works by damaging the DNA molecules inside the cancer cell, thereby preventing them from being able to grow and divide. Generally, this treatment is done on an outpatient basis in a hospital or clinic. The type of radiation to be used is determined by the location of the tumor in the body.
External Beam Radiation
This type of radiation therapy involves lying on a table while a machine delivers a beam of radiation from the machine, through the skin, to the tumor. The most common machine is called a linear accelerator. The exact location for the beam to “hit” is determined by calculations during the “simulation” visit prior to the initiation of radiation therapy. The radiation is given over several days (often between 4 and 14 days), with each appointment lasting about 30 minutes. The actual dose of radiation is given for seconds to minutes, but it takes time to get you and the machine set up to deliver the precise dose of radiation ordered by your doctor. The total number of days is determined by the amount of radiation that your doctor wants to use. Some areas of your body are more sensitive and will not require as much radiation as others.
External beam radiation therapy is used commonly to treat bone metastasis causing pain or areas of bone that have been weakened by the cancer (to prevent the bone from breaking). These areas include the ribs, femur (the upper leg bone), humerus (the upper arm bone), and vertebrae (your backbones). If a fracture (break) occurs, radiation therapy may be given to kill cancer cells in the bone, allowing the fracture to heal. When kidney cancer spreads to the femur or humerus, surgery may be done to insert a metal rod to stabilize the bone with radiation therapy being given following surgery.
Side Effects of Radiation Therapy
Unfortunately, radiation may also damage healthy, normal tissue. Side effects of radiation therapy occur in the area treated, referred to as the “radiation field.” These side effects are temporary and vary depending on the area of the body being treated. One of the most common side effects is dry, irritated (reddened) and sensitive skin. Your radiation oncologist or nurse will provide you with written information and instructions for skin care and other side effects specific to your radiation treatments. The skin may require 6 to 12 months to return to normal.
Constipation or diarrhea may occur if the intestines are in the “radiation field.” Anemia (low hemoglobin), neutropenia (low white blood cell count), and thrombocytopenia (low platelet count) may occur if you are receiving radiation therapy to the pelvic bones or femur. Nausea, vomiting, and urinary discomfort may also occur.
Certain side effects occur during or shortly after the completion of radiation, while other side effects may begin several weeks after you have completed radiation therapy. Fatigue may develop towards the end or shortly after your treatments have finished. Fatigue is not unusual, but it is important to discuss the timing and severity of fatigue with your doctors and nurses. Resting is important, but doctors usually advise patients to stay as active as possible.
It is important to ask questions before treatment starts, at appointments, and during your recovery from radiation in order to ensure that your treatments are effective, side effects are minimal, and that any side effects that develop can be treated early. All of these factors will help you tolerate the treatment with a minimum of side effects and complications.
Radiosurgery is non-surgical technique that allows treatment of cancer that has metastasized to the brain. Doctors direct beams of high-dose radiation to tumors. This allows for a more precise and concentrated treatment than other types of radiation. Radiosurgery is the preferred method of treating brain tumors under a certain size and number.
One form of radiosurgery is gamma knife therapy for brain metastases. This is an outpatient procedure done in a gamma knife center, using a fitted head frame and both a CT and MRI scanner. The patient lies on a bed wearing the fitted head frame (helmet) that slides into the gamma knife machine. Radiation is delivered through ports inside the helmet, with the beams intersecting at the tumor.
Chemotherapy works on the same principles as radiation therapy except that chemicals are used to kill malignant cells or slow their growth. The specific type of chemotherapy depends on the site of metastases, type and grade of tumor, and physical condition of the patient. Many chemotherapy programs combine several different drugs to kill malignant cells that might be resistant to a single drug. Chemotherapy may be administered in a hospital or on an outpatient basis. The drugs may be taken by mouth, by intravenous infusion, or by simple injection.
Although chemotherapy is the standard treatment for most solid tumors, kidney cancer is generally resistant to chemotherapy.35 The reason for the resistance of kidney cancer cells to chemotherapy is not completely understood. However, it is now known that kidney cancer cells produce an overabundance of multidrug-resistance-associated protein, which acts to repel various chemotherapeutic agents away from the cancer cell.
5-Fluorouracil (5FU) appears to be the most effective chemotherapeutic agent currently available for kidney cancer, but response rates are only in the range of 5% to 8%.36 Therefore, at present, chemotherapy is generally used in combination with other therapies or reserved for patients entering clinical trials to test new agents and for patients who failed to respond to immunotherapy.37 Researchers continue to study new drugs, new drug combinations, and new treatment approaches.
As in radiation therapy, chemicals can damage normal cells. As a result, patients may experience side effects such as nausea, vomiting, diarrhea, rash, allergic reactions, and low white blood cell counts. The severity of these side effects depends on dosage, the specific drug used, the patient, the course of treatment, and other factors. These effects may last for a few hours to a few days.
Hormone therapy is a form of chemotherapy; however, in this case natural and synthetic hormones are used in place of cytotoxic drugs. There are generally fewer side effects from this type of therapy. Unfortunately, to date the use of hormonal therapy in the treatment of metastatic kidney cancer has yielded disappointing results.36 Hormone therapy is generally used to treat symptoms of the cancer rather than the cancer itself in a small number of patients with advanced kidney cancer.38 Megace (medroxyprogesterone) is an oral hormonal agent which may be used to help treat cancer-related anorexia, or loss of appetite.
Vaccine therapy is an experimental treatment that uses the patient’s own tumor cells or tumor-associated products to vaccinate the patient. The goal is to boost the body’s immune system in order to fight cancer. Unlike other vaccines, which are preventative, cancer vaccines are therapeutic; that is, they treat the disease rather than prevent it. Once you have had surgery to remove a tumor, a portion of it is used to create a vaccine that is then re-introduced into the body. It is hoped that these naturally occurring substances will stimulate the immune system to attack any new cells that re-appear bearing the original tumor’s genetic code. Vaccine therapy using tumor cells should be discussed as a treatment option before your nephrectomy.
Vaccine therapy is still in an investigational stage, with numerous research programs in progress. Early results were mixed, but as techniques have evolved, results have become more promising. Oncophage®, a vaccine manufactured by Antigenics, is approved for use in Russia, but has not been approved by the FDA.
Stem Cell Transplants
Blood stem cells reside in the bone marrow and perform the critical role of continually replenishing the body’s supply of red blood cells, white blood cells, and platelets. When transplanted, stem cells and T-Lymphocytes can elicit an anti-tumor effect under certain conditions.
This is a highly experimental procedure, and patients with advanced metastatic cancer who did not respond to interferon alfa K2 therapy have been treated with transplantation of peripheral blood stem cells.51 The results of this approach remain experimental, and because of the serious side effects experienced by some patients, further refinement of the procedure is needed.
Stem cell transplantation is an intensive procedure and is only recommended in limited situations. Check with your doctor.
Managing Your Expectations of Therapy
As you and your medical team consider options, including all of the treatment therapies listed here, it’s important to keep all of these options in perspective. Your doctor will make a recommendation to you based on a number of factors. It is important to understand why a particular treatment is chosen, so be sure to ask questions. If you are unable to afford these treatments, financial help is available. Call +1 847-332-1051 for information.
The state of your disease will be followed through the use of scheduled CT scans. Your doctor will discuss your results with you, indicating whether the tests show stabilization, partial response, complete response, or progression of the disease.
Each of us wants and needs to believe that we will be helped and “cured” by whatever therapy is used. The information you receive may cause disappointment. However, make certain that you talk to your doctor to ensure that you understand the meaning of terms like “partial response” and “stable disease.” These should be viewed as partial successes, not failure. Partial responses can help you determine when to change therapies — sometimes leading to other options that are more beneficial. Even if there is no response to a given therapy – a condition known as “stable disease” – this may put you in a holding pattern until a newer treatment or clinical trial is available. Kidney cancer is too unpredictable, and the therapies are too new, for you to give up fighting because of “stable disease” or “partial response.” For this reason, it is important not to let disappointment rob you of your determination or will to live. Simply learn from your experience and go on.