• Paths of Progress Spring/Summer 2010

    Gaining Ground against Kidney Cancer

    New drugs benefit kidney cancer patients
    By Richard Saltus

    CT scans show that the anti-angiogenesis drug Sutent has helped patient Shaun Tierney (above) keep his advanced kidney cancer under control for several years.CT scans show that the anti-angiogenesis drug Sutent has helped patient Shaun Tierney (above) keep his advanced kidney cancer under control for several years. 

    When Shaun Tierney, a 51-year-old father of three, was diagnosed with kidney cancer, renegade cells had already spread to form colonies in his lungs and bones, giving him a "statistically grim" outlook.

    "When my doctor told me what the scan showed," he recalled, "she was teary-eyed."

    Kidney cancer (renal cell carcinoma) is notoriously resistant to chemotherapy and radiation, and therefore hard to treat unless caught early - which happens in only about half of all cases.

    If the cancer has spread and can't be completely removed surgically, survival rates drop sharply.

    Tierney, a former General Electric employee who lives in Pittsfield, Mass., said that when his tearful doctor gave him the bad news, his immediate reaction was to comfort her and say, "Just tell me what I have to do next."

    For Tierney and his wife, that next step was a consultation at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). They met with Oliver Sartor, MD, an oncologist from New Orleans who was practicing in Boston while his city's medical infrastructure recovered from the devastation of Hurricane Katrina.

    Sartor reassured Tierney, listing the fast-growing number of treatment options.

    "He told me, 'If we were sitting here six months ago, we'd be having a different conversation,'" Tierney says. "That's how fast he said things were changing."

    In recent years, drug options for kidney cancer treatment have rapidly expanded. Toni Choueiri, MD, director of the DF/BWCC Kidney Cancer Center, is exploring their potential impact.In recent years, drug options for kidney cancer treatment have rapidly expanded. Toni Choueiri, MD, director of the DF/BWCC Kidney Cancer Center, is exploring their potential impact. 

    Prior to 2005, there was just one FDA-approved drug for kidney cancer, interleukin-2. It was often ineffective. Since 2005, at least six new drugs have been approved by the FDA for the disease, with more on the way.

    Sartor laid out a comprehensive plan, including higher doses of radiation therapy than are routinely given.

    "I was just flabbergasted that this man took so much time and care to explain my situation," Tierney says. "I left there with the most powerful medicine, which was hope."

    Three years later, Tierney is back on the golf course. His cancer remains in check and stories like his are becoming more common.

    Half of all kidney tumors are found incidentally in CT scans performed for unrelated reasons – often resulting in earlier diagnosis and smaller tumors. Surgical techniques, including minimally invasive and robot-assisted procedures, are more precise and allow shorter recoveries.

    And, most promising, advances in understanding of the molecular culprits in kidney cancers are leading to new targeted drugs and therapeutic cancer vaccines.

    "These drugs are clearly helping patients," says Toni Choueiri, MD, who now manages Tierney's care and is director of the newly established Kidney Cancer Center at DF/BWCC. "We're seeing survival increases in metastatic disease. I don't think Sean would be alive now without Sutent [one of the newer medications]."

    Kidney cancer risk factors

    Kidney cancer is about twice as prevalent in men as in women, very uncommon in people younger than age 45, and highest in people between ages 55 and 84, according to the American Cancer Society (ACS). The median age at diagnosis is 65.

    Although smoking, some workplace exposures, and obesity are all risk factors, Choueiri says most cases stem from simply "bad luck" – random damage to an individual's DNA. In addition, people with the rare genetic disorder Von Hippel-Lindau (VHL) disease are at high risk for kidney cancer.

    The ACS estimated more than 57,000 Americans would receive a diagnosis of kidney cancer in 2009, making it the seventh leading cause of new cancers in men, and the eighth in women. Nearly 13,000 deaths were expected.

    But time of diagnosis remains critical. Patients whose tumors are confined to the kidney – termed stages 1 and 2 – have an 88 to 95 percent chance of surviving at least five years, depending on the size of the tumor.

    Kidney tumors develop in the lining of the minuscule tubes that filter waste products out of the blood as it passes through the kidney. Although the tumors are often ringed with cellular defenses like a medieval castle, they are also dependent on supplies of oxygen and nourishment from their surroundings.

    As they grow, tumors signal nearby blood vessels to sprout small new tributaries that weave themselves around and into the cancers to deliver nutrients; this process is called angiogenesis.

    kidney-3-360.jpgNew drugs attack kidney cancer by blocking anglogenesis – the growth of new, small blood vessels that feed tumors. 

    The need for nourishment makes even drug-resistant kidney tumors vulnerable to an attack on the network of vessels that supplies them.

    This "anti-angiogenesis" strategy is behind the new generation of drugs showing success in advanced kidney cancers. These compounds include Nexavar (sorafenib), Sutent (sunitinib), Avastin (bevacizumab), Votrient (pazopanib), Torisel (tensirolimus), and Afinitor (everolimus).

    They block the signal that spurs blood vessel growth around the tumors, potentially starving a tumor of blood and oxygen and halting its growth – or even shrinking the cancer.

    "I've been very fortunate since my diagnosis," says Tierney. "I've had no new cancers, no progression of the tumors, and considerable regression of the disease."

    His extended survival has come at some cost, however. Though billed as less toxic than standard chemotherapy drugs that kill tumors directly, angiogenesis inhibitors can be rough on patients.

    Side effects forced Tierney to take a disability retirement from his job. Among them: nausea, diarrhea, lack of sensation in his feet, fatigue, and periods when he has little appetite.

    However, researchers hope that newer angiogenesis inhibitors in development will be less toxic than many of the first-generation compounds.

    In some ways, his case is unusual. Tumors will often develop some resistance even to angiogenesis inhibitors. Tierney has continued to respond to Sutent for several years, and has not yet needed to switch to another anti-angiogenesis drug.

    Advances in kidney cancer surgery

    A CT scan of a healthy kidney. Kidneys filter waste from the bloodstream and control the level of certain helpful chemical substances.A CT scan of a healthy kidney. Kidneys filter waste from the bloodstream and control the level of certain helpful chemical substances. 

    Tracey Miller, 40, also a patient of Choueiri, was diagnosed in 2008 with metastatic kidney cancer that had spread into her inferior vena cava, a major blood vessel, and even into her heart.

    Surgeon Jerome Richie, MD, chief of urology at Brigham and Women's Hospital and a member of the Kidney Cancer Center at Dana-Farber/Brigham and Women's Cancer Center, removed Miller's right kidney and, in conjunction with a cardiac surgeon, delicately extracted the cancerous growth in the vena cava and the heart's atrium.

    Surgery like this continues to be the mainstay of treatment for kidney cancer - and it is undergoing constant improvement.

    Traditionally, surgeons removed the entire kidney containing a tumor. But today, "We're doing more and more 'partial nephrectomies,'" says Richie, the chief kidney cancer surgeon at DF/BWCC.

    "If we can save half or 60 percent of the kidney, it lessens the chance that a patient would need to go on dialysis."

    Surgeons now perform many operations laparoscopically: instead of a large "open" incision, they make several small slits in the abdomen, inserting miniature cameras and instruments operated from outside the body.

    In some cases, a surgical robot guided by a surgeon seated at a console assists with portions of the procedure.

    The benefits of this minimally invasive method are less pain, faster healing, and a shorter hospital stay, explains Richie.

    For small tumors, surgeons may use a relatively new technique called cryoablation, in which slender, cold-generating surgical probes are inserted into the tumor to freeze it.

    "[The probes] form little ice balls around the tumor," says Richie. "You repeatedly freeze and thaw the tumors, and they just crumble away and disappear."

    Since Miller's successful surgery, her scans have showed some spots of cancer. She has tried Sutent from time to time, but stopped taking it because of severe side effects.

    After the cancer spread to one of Miller's adrenal glands, Choueiri enrolled her in a clinical trial of an experimental antibody drug called MDX-1106. The drug blocks a molecule on tumor cells that some tumors use to prevent the immune system from attacking the cancer.

    So far, so good for Miller. "My first scans showed a 40 percent shrinkage of the adrenal tumor," she says. And the side effects? "None, zip, nada!"

    Patients like Miller and Tierney owe thanks to basic science investigators such as Dana-Farber's William G. Kaelin Jr., MD, who has spent 15 years identifying molecular targets for treatment.

    Kaelin has focused on the disrupted gene pathway in the rare VHL disease, which is also implicated in most "sporadic" (noninherited) kidney tumors.

    Such tumors are characteristically very "vascular," meaning they are surrounded and infiltrated by a dense network of blood vessels, and the tumors produce a large amount of VEGF - an angiogenesis-promoting growth factor.

    This is because, as Kaelin showed in a 1996 report, the VHL protein normally keeps VEGF levels in an appropriate range, but when the VHL protein is mutated (as in VHL disease and kidney cancer), VEGF levels can rise sharply.

    "Early on, pharmaceutical companies started making VEGF inhibitors, and I had advocated that kidney cancer be a proving ground for VEGF inhibitors," Kaelin says.

    The idea is now bearing fruit in the surge of new drugs that are helping patients live longer.

    In addition, newer, more-specific angiogenesis blockers that may have fewer side effects are in the drug company pipeline, according to Kaelin.

    "These look exciting, and will be the foundation moving forward," he says. "I think the future will be 'smart' combinations of these and other drugs for this disease."

    New surgery options can save kidney function

    putting a freeze on kidney cancer  

    Surgeons often remove the entire kidney to treat tumors larger than 1.5 inches, leaving the patient with one working kidney. For smaller tumors, newer alternatives such as cryotherapy (freezing) and partial nephrectomy (tissue-sparing surgery) can preserve some function in the cancerous kidney, which may avoid the need for dialysis. These procedures can also lessen discomfort, reduce hospital stays, and lower costs.

    Putting a freeze on kidney cancers

    Patients with small, isolated tumors may be candidates for cryotherapy - freezing the cancer to destroy it. Slender, hollow instruments called cryoprobes are inserted through the skin into the tumor, and liquid nitrogen at minus-130 degrees F circulates through the probes.

    The process freezes the entire tumor, which becomes a ball of ice, while sparing normal tissue. The tumor is allowed to thaw, then is frozen again, after which it shrivels and dies.

    putting a freeze on kidney cancer  

    Cutting less, saving more

    Removing an entire cancerous kidney (radical nephrectomy) requires the remaining kidney to do all the work of removing wastes from the bloodstream. If anything happens to that kidney, the patient may need dialysis.

    A newer option is the "partial nephrectomy" in which surgeons remove just the tumor and some surrounding tissue, preserving 50 percent or more of the kidney's function. Younger patients with smaller tumors are candidates for this option.

    Paths of Progress Spring/Summer 2010 Table of Contents 

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