A new surgery, new drugs, and new hope

By Debra Wood, RN

Paula Bowen attributed the ache in her side to too much water-park or jet-boat activity. But months later, after severe back pain awakened the New Yorker, she learned the culprit was a huge mass in her kidney, a cancer that had spread to her lymph nodes.

A diagnosis of cancer is a bit overwhelming,” admits Bowen. Not panicking, she learned all she could. “I became active in my care.”

Bowen successfully fought her cancer, and, despite a recurrence in 1995, has lived with stable disease for seven years. Not as common as many malignancies, kidney (renal) cancer will affect more than 30,000 people this year, according to W. Marston Linehan, MD, chief of the Urologic Oncology Branch at the National Cancer Institute (NCI), Bethesda, Maryland. An estimated 12,000 will die of this disease.

“Kidney cancer is not a single disease, but a number of different types of cancer that occur in the kidney,” Dr. Linehan says. “The most common is clear cell at 70%. Other types include papillary, chromophobe, oncocytoma, and, more rarely, collecting duct and medullary carcinoma of the kidney. Kidney cancer can occur in both a sporadic, or noninherited, as well as a hereditary form.”

Kidney cancer lurks silently, producing few, if any, symptoms. Those symptoms that do occur are often readily attributed to something else, meaning the cancer may have advanced by the time it is diagnosed and fewer options for treatment are available. Many cases, like Bowen’s, are diagnosed late, after the cancer has spread.

Bill Bro from Peoria, Illinois, suffered from intractable back pain, which doctors attributed to muscle aches. Today, Bro knows that was a warning sign of kidney cancer. Eventually Bro sought medical care when he spotted blood in his urine, and doctors found a small, localized tumor.

“The urologist pronounced the renal cell carcinoma as a death sentence,” recalls Bro, who sought a second opinion at a major medical center where doctors removed his right kidney in a procedure called a nephrectomy. He has been cancer-free and without back pain for 13 years.

Surgery—The Definitive Treatment
Performing a nephrectomy remains the primary treatment for kidney cancer caught before spreading to distant regions of the body. Most often, the surgeon performs a radical nephrectomy, removing the whole kidney along with the adrenal gland and the tissue around the kidney. Some lymph nodes in the area may also be removed. In some cases, the surgeon removes only the kidney (simple nephrectomy). The remaining kidney generally is able to perform the work of both kidneys. In another procedure, partial nephrectomy, the surgeon removes just the part of the kidney that contains the tumor.

“When patients are treated with early-stage disease, we have a very high 10-year survival rate,” Dr. Linehan says. “They have a 95% chance of not having tumors recur within 10 years.”

Today, surgeons often perform the nephrectomy laparoscopically, making several small incisions through which they insert instruments that allow them to view the surgery field. Patients typically report less pain and recover faster.
A procedure called a hand-assisted laparoscopic nephrectomy has shown to be as effective as an open surgery for kidney cancer. During a hand-assisted procedure, the abdomen is slightly inflated and the surgeon makes an additional incision about 3.5 inches long, through which the kidney is removed manually (see illustration).

Some patients with small tumors may be candidates for a partial nephrectomy. In these cases, only the tumor and a portion of the kidney are removed. Surgeons at the NCI are evaluating the role of minimally invasive, organ-sparing techniques such as partial laparoscopic nephrectomy and other treatments.
Standard treatment for advanced disease

As kidney cancer grows, it may invade organs near the kidney (liver, colon, or pancreas) or spread (metastasize) to other parts of the body, most often the bones or lungs. If kidney cancer spreads to the lungs, the cancer cells in the lungs are metastatic kidney cancer, not lung cancer. Kidney cancer often is resistant to conventional chemotherapy, a mainstay in most cancer treatment, so doctors are looking at other medical therapies.

Proleukin® (interleukin-2 or IL-2), an immunotherapy protein that activates the immune system to destroy the cancer (see CURE, Spring 2003), is the only drug approved by the U.S. Food and Drug Administration (FDA) to treat advanced-stage kidney cancer.

“IL-2 works for only 15-20% of people, and about half of those will have durable remissions,” says Robert Figlin, MD, Division of Urologic Oncology, David Geffen School of Medicine, University of California, Los Angeles. “And it’s a potentially toxic treatment that must be given in the hospital by experienced clinicians.”

Dr. Figlin has investigated patient characteristics that may help in identifying who will likely respond to IL-2. In general, patients functioning well with minimal metastases and no other diseases are better candidates. High doses are required to obtain lasting remissions.

You are more likely to benefit when your overall health is good, Dr. Figlin says. “The reason for that is you probably have a more intact immune system to respond to IL-2. Waiting until you have symptoms will make you less likely to benefit from IL-2 treatment.”

Shortly after her nephrectomy, Bowen began receiving low-dose IL-2 four times a week for four weeks, with a two-week interlude. The therapy continued for a year and resulted in significant side effects.

“It felt like the worst case of the flu,” Bowen explains. “It’s a constant sort of ache. The side effects are cumulative, and the longer you are on therapy, the worse you feel.”

Cognitive dysfunction associated with the therapy eventually forced Bowen to leave her job at a university. Other side effects can include low blood pressure, fluid accumulation, diminished kidney function, heart damage, intestinal bleeding, fever and chills, nausea, and vomiting. Side effects are temporary and reversible, but they limit the use of IL-2 therapy to selected patients treated by experienced healthcare teams.

Treatments on the Horizon
Although not yet approved for treating kidney cancer, Thalomid® (thalidomide), the drug used decades ago for morning sickness, is now being investigated as a treatment for a number of cancers. The drug was pulled from the world market in the 1960s after it was confirmed that it caused birth defects. Ironically, the same mechanism thought to have produced the birth defects, inhibiting blood vessel creation in a process called angiogenesis, has proved helpful in decreasing tumor size by blocking the tumor’s supply of oxygen and nutrients. The drug also weakly inhibits a growth factor and enzyme associated with solid tumors.

Robert J. Amato, DO, associate professor of urology, Baylor College of Medicine, Houston, pioneered using thalidomide to treat kidney cancer in patients who had not responded to prior therapies. A review of his studies and other phase II studies showed a partial response in up to 17% of patients and stabilized disease in 17-64% of patients, Dr. Amato says. Side effects include constipation, lethargy, and, with long-term use, neuropathy, which is the loss of feeling in the hands or feet. Dr. Amato is investigating thalidomide in combination with IL-2 in phase III trials, and other researchers are combining it with other drug combinations.

Targeting Kidney Cancer
Other targeted therapies also hold promise in treatment of kidney cancer. While some drugs in this class have been approved for other cancers, research continues for renal cell carcinoma.

Avastin™ (bevacizumab) neutralizes a hormone called vascular endothelial growth factor (VEGF), which is made in kidney cancer to promote growth of blood vessels.

During clinical trials conducted by the NCI, researchers found that Avastin slowed the average time it took for tumors to grow by about two months, and patients tolerated the drug well. The study showed that antiangiogenic drugs such as thalidomide and Avastin can be effective in advanced human cancers.

“It also showed that Avastin, for tumors where VEGF is important, is an effective blockade,” says James C. Yang, MD, a senior investigator at the NCI. “This is the first step toward generating real treatments that will have obvious benefits for patients with advanced cancer.”

The drug has also shown promising results in studies with colorectal cancer and for that reason has been awarded fast-track status by the FDA. Avastin’s target, VEGF, may also be important in the development of blood vessels in those diseases. Kidney cancer may be an excellent proving ground for Avastin, since a genetic mutation that causes the cancer also triggers production of VEGF.

Dr. Yang says Avastin will likely be used in combination with other types of treatment, combinations that may not only enhance its effectiveness in kidney cancer, but impact other types of cancer not responsive to Avastin alone. He plans to search for other hormones that tumors use as backups and block them as well.

Monoclonal Antibodies
Another potential treatment, the monoclonal antibody ABX-EGF, targets epidermal growth factor receptor (EGFR). Overexpression of this growth factor receptor, on which cancer cells depend for survival, has been found in more than 70% of kidney cancers. ABX-EGF blocks the ability of the epidermal growth factor to bind with its receptor.

Doctors give the antibody weekly during an hour-long, intravenous injection. Dr. Figlin says patients, who experience few side effects, continue on the drug as long as they are benefiting.

“In phase I and early phase II trials, there has been activity against kidney cancer,” says Dr. Figlin, who was a principal investigator in the clinical trials.

Blocking Cell Division
Another targeted agent under investigation, CCI-779, blocks certain cells from dividing. In current studies, the drug is used alone, and some patients have taken it for a year or longer. It may be combined with other drugs in future research. Side effects include skin rash and nausea.

“It has shown that it can produce tumor shrinkage in a substantial minority of patients with renal cancer,” says Michael Atkins, MD, associate professor at Beth Israel Deaconess Medical Center, Boston. “Although most tumor shrinkage is minor, a few patients have partial responses. And it may delay time to progression for the group as a whole.”

Bone Marrow Transplant
Researchers are also treating kidney cancer with immunosuppressive drugs followed by transplants of stem cells and white blood cells donated by a healthy sibling of the patient. The therapy may be associated with severe complications, but doctors have observed significant response rates, including in some cases tumor shrinkage in patients who have failed to respond to conventional therapies, such as IL-2 or interferon alpha.

In an NCI trial of 19 patients, three had total regression of all metastases and seven experienced a partial regression of the tumor. Two patients died of complications from the transplant therapy. A substantial part of the research now focuses on methods to limit the side effects and toxicities that may follow the transplant.

“This is a novel form of immunotherapy that harnesses the powerful anticancer effects of immune cells obtained from healthy siblings without cancer,” said Richard W. Childs, MD, senior investigator, Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland. “We are obviously happy that some patients have had meaningful regression of their cancer following the transplant. However, until we are able to develop a transplant strategy that is associated with less risk of life-threatening toxicities related to the procedure, the approach will likely remain investigational and be limited to patients who have failed conventional therapies.”

These studies represent a sampling of promising treatments in the works, made possible through science and the cooperation of patients willing to participate in their testing. In addition, Dr. Figlin believes clinical trials offer patients the best available care.

“For kidney cancer, it is critical that all patients participate in clinical research,” says Dr. Figlin. “That is the only way to change the natural history of this disease.”