Warming up to hyperthermia: heat therapy could improve existing cancer treatments.

In March 1999, Jason Foster was unpleasantly surprised by a BB-size lump that he found in one of his testicles. He ignored it for a week, hoping that it would go away. But instead, the lump swelled to the size of a pea. "I had alarm bells going off in my brain," recalls Foster. A trip to the urologist confirmed his fears--Foster had testicular cancer. The news set him on a grueling, 4-month path of surgery and multiple chemotherapy drugs. Foster lost his hair, spent hours throwing up, and was exhausted. To stay upbeat, he tried to keep the disease in perspective.

"I knew I'd have a positive outcome on the other side," says the 36-year-old media-relations director at San Diego State University. "I still think of myself as having had minor league cancer. Those with breast, lung, and other cancers, they go through treatment, and there's no guarantee that they'll make it."

Foster's take is correct: Among cancers, testicular cancer is unusually curable. Even when the cancer has migrated elsewhere in the body by the time of diagnosis, about 72 percent of men are still alive 5 years later. In contrast, the 5-year survival rate for breast cancer is about 26 percent after it spreads.

Researchers have puzzled for years over what they call the "Lance Armstrong effect," named after the world's most famous bicycle racer and testicular cancer survivor. Some scientists propose that a single factor--heat--could be responsible for this cancer's relatively easy cure. Testicular cells normally stay a couple of degrees cooler than other cells in the body. The cooler cells can't survive normal body temperatures, and researchers speculate that they retain this vulnerability even when they become cancerous and spread to other parts of the body.

"The hypothesis is that that slight temperature change is enough to put them on the cliff's edge, so just a slight nudge from chemotherapy or radiation makes them die when they wouldn't die otherwise," says Theodore DeWeese, a radiation oncologist at Johns Hopkins University.

Researchers have applied this principle to other types of cancers. By simply ratcheting up a tumor's temperature a few degrees--similar to the tiny temperature difference between the testes and the rest of a man's body--scientists are boosting the power of radiation, chemotherapy, and cancer vaccines. Armed with a better understanding of how heat amplifies those treatments' effects and with new tools to heat tumors, researchers may someday give every cancer patient the bright prognosis of Foster, Armstrong, and other testicular cancer survivors.

HEATING UP The idea of prescribing heat, or hyperthermia, to cure whatever ails you spans hundreds of years, says cancer researcher Donald Coffey of Johns Hopkins University in Baltimore. "There's no culture in the world that doesn't believe that hot springs and baths are good for you," he adds.

In the late 1800s, a New York bone surgeon named William Coley discovered that cancer patients who came down with infections--and fevers as a consequence--sometimes experienced remissions. He achieved similar results by injecting patients with bits of bacterial cell walls, which prompted fevers without infections' other dangers.

Almost a century later, in the 1970s and 1980s, researchers renewed attempts to kill tumors by heating them with microwaves, ultrasound, or other methods. "We had our sights set on killing tumor cells directly to make hyperthermia effective," says radiation biologist Mark Dewhirst of Duke University Medical Center in Durham, N.C.

As researchers developed more-accurate ways to measure internal temperature, they made a surprising discovery. "We found out that temperatures too low to kill cells were quite effective in sensitizing tumors" to other treatments, Dewhirst says. Temperatures that were a mere 2[degrees]C to 9[degrees]C warmer than body temperature could make a difference for cancer treatments.

It's not clear how higher temperatures sensitize cells. One possibility is that heating improves a tumor's blood flow, delivering more chemotherapy drugs to cancer cells. Better blood flow also delivers more oxygen, a pivotal ingredient in making radiation treatments effective.

Heat also deforms the vast array of proteins necessary for normal cellular functions, explains radiologist Joseph Roti Roti of Washington University in St. Louis. Some proteins bend when warmed, exposing molecular segments that stick to other proteins. "This is like putting rust in the machinery," he says.

Hotter temperatures also seem to have a dramatic effect on the immune system, says immunologist Elizabeth Repasky of Roswell Park Cancer Institute in Buffalo, N.Y. Studies in her lab and elsewhere' have shown that fever-range temperatures increase the infection-fighting ferocity of immune components such as dendritic cells and macrophages. Such an increase in immune power could also potentially fight off tumors, Repasky says.

However, some researchers suggest that the most convincing explanation for hyperthermia's effects is that the cellular nuclear matrix is damaged by heat. The structure, which stretches like a spider web throughout each cell's nucleus, is pivotal for DNA replication and the first step in translating genetic information into the proteins that a cell needs to function. Although cancerous testicular cells survive higher temperatures than healthy testicular cells can, normal body temperatures damage the nuclear matrices of both types of cells, says DeWeese. The added damage from radiation or chemotherapy kills the cancerous cells.

Heat also damages the nuclear matrices in other cells, DeWeese adds, though it takes a higher temperature than that of the body.

"The challenge is, what is that deadly temperature for prostate cancer or breast or lung cancer?" asks DeWeese.

SIZZLING STUDIES Regardless of heat's mechanism, clinical trials of hyperthermia have delivered promising results.

In trials reported in the May 2005 Journal of Clinical Ontology, Dewhirst's team showed that heat treatment could amplify radiation's effects. The scientists recruited 109 cancer patients with superficial tumors, such as those in the skin of the head, neck, or breast. Half the patients received radiation alone, and the other half received radiation plus two weekly sessions of hyperthermia treatment.

After several months, the researchers found that about two-thirds of the patients in the hyperthermia group showed no lingering signs of their cancer. In contrast, only 42 percent of patients receiving just radiation had that response.

Dewhirst and his colleagues are currently juggling three other hyperthermia clinical trials: one for cervical cancer that's spreading, another for breast cancer that's recurred on the chest wall, and a third for advanced sarcoma, a cancer that arises in muscles, fat, and other soft tissues.

Dewhirst and his team usually work with the same type of microwaves that people use to heat leftovers. Penetrating only about 3 or 4 centimeters into tissue, the microwaves warm tumors in the skin, breast, chest wall or limbs, and on the cervix.

In a typical hyperthermia treatment at Dewhirst's lab, several microwave antennas are strapped to a patient's body directly over a tumor. These antennas are adjusted to direct the microwave beam. The researchers put a small catheter inside the tumor to monitor its temperature. The researchers warm the tumor to between 40[degrees] and 43[degrees]C (104[degrees] to 109[degrees]F) and keep it there for about an hour. Patients typically get this treatment once or twice a week in conjunction with radiation or chemotherapy.

Repasky is harnessing hyperthermia in a less direct way: by exploiting its effects on the immune system. She notes that several studies have suggested that cancer vaccines can tune the immune system to fight existing tumors. She and her team wondered whether heating the whole body might increase cancer vaccines' effectiveness by making the immune system a more efficient fighter.

To test the hypothesis, Repasky and her colleagues John Subject and Sherry Evans, also of Roswell Park, administer a cancer vaccine to mice with a form of breast cancer. Then once a week, the researchers place some of the mice in a warm box to raise each animal's core temperature to about 39[degrees]C, which mimics a low fever.

The researchers haven't yet published their findings from such experiments, but Repasky says that the heat seems to turn cancer vaccines into more effective weapons against the disease. "Our preliminary data suggest that this is worth moving forward on," she says.

Like Repasky, Joan Bull of the University of Texas Health Science Center in Houston is using full-body heat to treat cancer. Her team has found that warming people to feverlike temperatures seems to amplify the effects of chemotherapy.

In ongoing clinical trials, patients get one type or more types of chemotherapy. Then, a day or two after taking the drugs, each patient climbs into a bed equipped with an overhead infrared heat lamp. Once a patient reaches a core temperature of 40[degrees]C, he or she gets wrapped up "like a mummy" in blankets that maintain the temperature for about 6 hours, Bull says.

In one trial of eight patients with advanced pancreatic cancer--a disease that typically kills its victims within 4 months of diagnosis--five people had at least some regression of their disease. In other clinical trials, Bull anal her team are investigating timing options for hyperthermia treatments and combining it with drugs.

Coffey and his colleagues, including DeWeese and Robert Getzenberg of Johns Hopkins, are trying a more targeted approach: heating cancer cells from the inside out.

The team's efforts rely on iron nanoparticles, tiny bits of metal that are already used as contrast agents in some medical-imaging techniques. The researchers' strategy is to tag the nanoparticles with antibodies or other molecules and have the immune system guide the particles directly to cancer cells. Once the iron enters cancer cells, a magnet would heat the cells a few degrees above normal body temperature. Getzenberg and his colleagues outline their approach in the July 26 Journal of the American Medical Association.

The researchers recently started testing the strategy in mice implanted with human-prostate tumors.

HOT NEW TREND? With more and more experiments showcasing hyperthermia's potential, the National Cancer Institute (NCI) is devoting a substantial amount of grant money to the cause, says Rosemary Wong, who directs NCI's division of cancer treatment and diagnosis. Wong notes that hyperthermia could carve itself a niche in regimens for attacking some cancers that can't currently be effectively treated, such as extremely aggressive tumors and those too advanced to be surgically removed.

"If a tumor is already resistant to chemotherapy or radiation or is very advanced, then you need to try something new," she says.

However, Wong notes, hyperthermia still has far to go before it becomes a standard therapy. Researchers need to optimize the temperature range and the methods for applying heat for each type of cancer. Improved ways to measure temperature and to keep it constant could also take hyperthermia to the clinic faster.

Scientists might find ways to make heat even more devastating for cancer cells, says cancer researcher Dennis Leeper of Thomas Jefferson University's Kimmel Cancer Center in Philadelphia. When cells heat up, he explains, protective molecules called heat-shock proteins spring into action. Various interventions, such as adding drugs or changing a cell's pH, can make heatshock proteins less efficient. This could amplify the consequences that heat has on cellular proteins, perhaps leading to hyperthermia methods that harm cancer cells at lower temperatures.

Such measures could eventually make cancer cells as easy to kill as those that plagued Foster, who this past July celebrated 7 years without a recurrence of his cancer. Regardless of heat's role in his treatment, Foster says that he feels lucky to be alive. In the future, he hopes that other cancer patients can be just as lucky.