Kidney cancer is highly resistant to the chemotherapy drugs traditionally used to fight other cancers and is often not detected early enough for any form of treatment to be curable, so it is no surprise that most kidney cancer patients don’t live long enough to truly be considered ’survivors.’

Two drugs approved for use in the US since December 2005, however, have demonstrated benefit in shrinking kidney cancer tumors and also in delaying the time it takes for new tumors to develop. The drugs, marketed under the brand names Nexavar and Sutent, are not cures for the disease, but a Medical College of Wisconsin cancer specialist explains that they have already had a significant impact in the field of renal cell carcinoma treatment and may ultimately prove to extend survival time for patients.

“We are on the right track, learning more all the time about the biology of kidney cancer tumors and about how to disrupt that biology,” said Nancy B. Davis, MD, Medical College Assistant Professor of Medicine. “Kidney cancer is pretty rare in the US and in the rest of the world. Although there are a couple different kinds of kidney cancer; the most common kind is sporadic, meaning that it is not genetically transmitted.

“There is a hereditary form of kidney cancer that involves a particular genetic mutation. Those cancers tend to occur early, in people in their 30s or 40s, and tend to be hereditary, meaning that other family members have had that kind of kidney cancer. The vast majority of kidney cancer, however, is not hereditary.”

While kidney cancer may be rare compared to other cancers, the National Cancer Institute (NCI) of the National Institutes of Health estimates that in the US more than 51,000 new cases will be diagnosed and nearly 13,000 people will die from the disease in 2007.

Usually Detected in Advanced Stage

“The risk factors for kidney cancer are not well defined,” said Dr. Davis, “although we do know that smoking is related to kidney cancer and that some toxin and chemical exposures can lead to kidney cancer. But overall it is difficult to determine why a particular person got kidney cancer. Most of the time we can’t make that determination.

“Kidney cancer typically grows slowly. The classic literature will tell you that the tumors present with blood in the urine, back pain, an abdominal mass. But that happens in less than 10% of the people with kidney cancer. A tumor must grow large enough to cause any of those findings, so these findings don’t occur until late, if ever. When we find kidney cancer, it usually has been asymptomatic (presenting no obvious signs of disease), and may be quite large and quite advanced.

“A very early diagnosis is needed in order to cure kidney cancer. It can be cured if detected soon enough, with surgery to completely remove the tumor. But even in patients with early-stage disease, small tumors less than four centimeters that can be taken out completely, about 5% will recur. Once it is metastatic (moves to other areas) it is rarely curable.”

Chemotherapy Agents Have Little Impact

In simple terms, kidney cancer kills by spreading to other parts of the body and causing organ failure. It is most often treated with radical nephrectomy, in which a surgeon removes the entire kidney, possibly the adrenal gland and some tissue around the kidney. In Stage 1 kidney cancer patients, simple nephrectomy may be employed to remove just the kidney. Patients with only one kidney or with cancer in both kidneys, or with small tumors of less than 4 centimeters (about three-quarters of an inch) may have a partial nephrectomy, with only a part of the kidney removed.

Other kidney cancer treatments include arterial embolization (a substance is injected into the renal artery that inhibits blood flow and thereby starves the tumor of oxygen and other things it needs to grow), radiation therapy (high-energy rays used multiple times over several weeks to kill cancer cells), and immune therapy (using the immune system’s natural ability to fight cancer by introducing large quantities of interleuken-2, which is normally produced in the body in small amounts to fight infection and disease). The use of immune therapy is decreasing since the approval of newer, more targeted, drugs.

Kidney cancer is essentially non-responsive to chemotherapy, a mainstay of treatment for many other cancers. “Kidney cancer does not respond to typical chemotherapy agents that we consider for disease like breast cancer or lung cancer,” said Dr. Davis. “Those agents get into the cell and stop cells from growing and dividing by intercalating into their genetic code.

“When a cancer cell is growing very slowly, cell division is not taking place and the cells are not susceptible to intercalating agents. Chemotherapy agents don’t work well in slow-growing tumors, including kidney cancer and myeloma (a primary tumor of the bone marrow). If the drugs can’t get in, it’s hard to kill it.”

Nexavar and Sutent Block Cell Growth

The immune-modulating medication interleuken-2 has low response rates, said Dr. Davis. Statistically, she said, only about 15 out of every 100 kidney cancer patients will have shrinkage in their tumor using high-dose interleuken-2 and, out of those 15 patients; fewer than one may have a prolonged remission or potential cure. For a variety of reasons, including significant side effects, only a very select group of young, otherwise healthy patients are candidates for interleuken-2 treatment.

Survival rates among kidney cancer patients are similarly grim. While by no means certain in terms of accuracy for any individual patient, said Dr. Davis, patients with metastatic kidney cancer but with none of the characteristics in a validated five-factor predictive model have a median survival of 20 months, patients with one or two of the five factors fall into a survival range of about 11 months, and patients with three or more of the factors have a median survival of 4 months.

Having new drugs that show promise for providing benefit to a higher percentage of kidney cancer patients is a big step forward, said Dr. Davis. She noted that the Medical College was involved in the global study just prior to Nexavar’s approval and is currently engaged in other major kidney cancer studies. One is a trial of the two new drugs in the post-operative setting “to see if we can decrease the recurrence rate in patients who are at higher risk,” and the others involve earlier phases of research into two other new agents.

“Nexavar and Sutent are both orally available medications that block cell growth and proliferation at a molecular level,” said Dr. Davis. “They target receptors called tyrosine kinases on the cancer cells. Blocking these targets prevents new blood vessel formation and tumor proliferation/growth. These medications really have radically changed the treatment of renal cell carcinoma. We have two more therapies, in addition to immune therapy, that, while they do not cure kidney cancer, are fairly well tolerated and can provide tumor response (meaning shrinkage of tumor) and also delay time-to-tumor progression. While neither drug has statistically met a survival endpoint, with further follow up they may prolong life in an advanced kidney cancer population.

“It’s a very exciting time in kidney cancer treatment development and research. Just in the past 18 months we’ve gone from having pretty ineffective yet highly toxic therapies to offer, to having two oral drugs which are fairly well tolerated and do show benefit. Currently there are ongoing clinical trials investigating newer agents and new combinations of agents. We don’t have a cure, so we’re not anywhere near the end of research and development for this disease. But the new agents that are available now and those coming along provide us further options for these patients.”

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