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DURHAM, N.C. -- Writings from the ancient Egyptians claim they used an instrument called a "fire drill" to cauterize cancers, but 3,000 years later doctors have not yet mastered the art of directing heat to the desired spot to kill cancers. Targeting a tumor deep within the body or a limb is like trying to bake a single cookie in an oven that remains cool to the touch, say researchers at Duke University Medical Center's Hyperthermia Program. Thus, practical barriers have stymied the widespread use of heat to shrink tumors: the tumor is hard to access, the target is hard to hit and physicians cannot easily measure its temperature.

Recently, the Duke program received a $19 million continuation grant from the National Cancer Institute (NCI) to study and apply the benefits of using heat, or hyperthermia, to treat patients with cancer. The grant is currently entering its 19th year of continuous funding and, according to program members, Duke has the only federally funded research program dedicated to making heat treatment a viable option for patients with a wide variety of cancers.

The new funds are helping the program's researchers refine modern-day tools to implement the ancient idea of "targeted fire" to kill cancers. They are using microwave antennae to beam heat at a precise spot in the body; leg cuffs that encircle the affected area and deliver targeted heat; and a miniature water Jacuzzi that transmits microwave heat selectively to cancerous breasts.

Such modern inventions – many developed and built at Duke -- are enabling physicians to more effectively employ heat to target and destroy tumors. As a result, studies at Duke and elsewhere have demonstrated that hyperthermia boosts the killing power of radiation and chemotherapy by up to ten times greater than without heat. When the tumor reaches the desired temperature, physicians blast it with chemotherapy or radiation.

"The question isn't whether hyperthermia works, but how do we apply the therapy so it achieves the desired goal and how do we inform physicians on its proper use," said Mark Dewhirst, DVM, Ph.D., professor of radiation oncology at Duke and director of the hyperthermia program. "Our goal is to enable doctors to write a dose prescription for heat treatment that is user-friendly and can be 'filled' as we would any other prescription."

During the past year alone, Duke researchers demonstrated precisely how heat can dramatically increase the ability of radiation to shrink recurrent tumors in the breast, chest wall, head and neck and skin. In addition, a Duke pilot study showed that a combination of hyperthermia, radiation and chemotherapy caused a complete clinical response in 10 of 12 patients with locally advanced cervix cancer, meaning the tumors shrank to insignificant size.

Heating tumors elicits a series of important changes that hasten the tumor's demise, said Dewhirst. Heat makes blood vessels leakier and thus enables chemotherapy to penetrate the tumor more effectively. Heat also increases oxygen levels within the tumor, and oxygen is critical to the proper functioning of radiation and chemotherapy inside a cell. Finally, heat amplifies the level of DNA damage that chemotherapy and radiation inflict upon the cancer cell by inhibiting enzymes that normally repair such DNA damage.

Still, persistent roadblocks have made hyperthermia difficult to administer and even harder to control and measure, said Dewhirst. Physicians lack clear-cut guidelines that dictate optimum temperatures and heating times for specific cancers. Technological and physical barriers have prevented physicians from determining whether the heat is reaching its intended target and, if so, how to accurately measure the tumor's temperature. As a result, doctors have not been able to deliver a uniform heat dose for all patients, he said.

Dewhirst's team has turned to the exquisite imaging capabilities of magnetic resonance imaging (MRI) to better visualize the tumor's location and gauge its temperature in real time, as it is being heated. A twist on the traditional MRI, the Duke team of biomedical engineers, physicists and radiation oncologists have created the MRI "imaging thermometer" that measures a tumor's temperature by measuring, in part, how fast water moves around the tissue. Because water moves faster when heated, the MRI detects this shift and depicts the hot spot as a red glow on the computer screen. When optimum temperatures are reached, the tumor is then treated with radiation or chemotherapy.

"We essentially create a three dimensional temperature map using the color red to depict the hottest region and blue to depict the coldest, so we can see exactly what we are heating and how hot the tumor becomes," said Dewhirst.

The new imaging thermometer is part of a dedicated MRI device used exclusively for hyperthermia treatment, he said. The NCI grant will allow the Duke team to fine-tune the device so it can be developed as an attachment to existing MRIs, allowing a broader range of treatment facilities to offer hyperthermia.

Indeed, Duke engineers have built a variety of devices that enable physicians to better target and heat tumors. Among the latest designs is a hyperthermia "cuff" that surrounds limbs that contain tumors, said Dewhirst. The cuff is a cylindrical tube with multiple antennae inside. The patient places the affected arm or leg inside the tube and doctors adjust each antenna to aim the microwave energy toward the tumor. Precisely aiming the heat at the tumor ensures the heat reaches its intended target.

"We know where we want the hot spot to be," said Dewhirst. "The issue is how to tune the heating device to deliver the heat to the right spot. Now we have developed a way to tune the microwaves so that we can target the right spot with the right dose."

For breast cancer patients, Duke engineers have designed a hyperthermia treatment table with a small opening through which the cancerous breast protrudes. The patient lies face down while the breast, resting in a small cup of water, is heated via microwave energy. The heat triggers the chemotherapy that has just been infused to settle inside the tumor. Once there, it trickles out of its protective coating -- a tiny fat bubble called a liposome – and attacks the tumor's genetic machinery. The body's normal tissues remain unheated, so the drug is not preferentially delivered there

"Encapsulating the chemotherapy inside of liposomes enables us to deliver 30 times more chemotherapy than we normally could to the tumor site, without poisoning the rest of the body," said Duke oncologist Kimberly Blackwell, M.D., who leads the studies using this new technology. "Heat also boosts the drugs' potency by interfering with mechanisms that control a cancer cell's ability to replicate."

Heat, while powerful, is only part of the equation, said Dewhirst. The tumor itself provides a highly sophisticated network of signals – a so-called microenvironment -- that drives how the tumor behaves in response to the treatment. Heating a tumor produces different results than heating normal tissue; thus, Dewhirst's team is studying how a tumor's oxygen levels, pH, glucose levels and other characteristics affect its response to heat.

INTO THE CLINIC

Armed with the latest technology, the Duke team has initiated a range of new studies to assess hyperthermia's ability to treat a wider variety of cancers. Among the latest Duke trials are studies examining:


• Hyperthermia and cervical cancer -- Although easily treated in the U.S.in its early stages, locally advanced cervical cancer is the number-one cancer killer of women worldwide. The cure rate in the U.S. is considerably reduced among women whose cancer is not diagnosed in its early stages. Duke is conducting an international phase III study in the U.S. and Europe, adding hyperthermia to the current standard of care for advanced cervical cancer to determine whether the addition of heat reduces mortality.

• Hyperthermia and breast cancer -- Women with chest wall recurrences of breast cancer will receive the Duke-developed heat-sensitive fat liposome containing the drug doxorubicin in a phase I trial. Subsequently, the drug will enter a phase I/II trial in women with locally advanced breast cancer. Currently enrolling are phase I/II trials for women with locally advanced breast cancer to receive the commercially-available liposome, Doxil.

• Genetic studies of locally advanced breast cancer -- Researchers will create genetic profiles of breast and cervix cancer tumor tissue to try to determine if certain genetic traits can predict recurrence after chemotherapy treatment. The researchers will study markers of low oxygen levels in tumors, which often are associated with poor outcome, and elevation of genetic markers of inflammation, another predictor of poor outcome.

• Sarcoma -- Two clinical trials for patients with tumors of connective tissue in the arms or legs (sarcomas) will test the Duke-designed heat delivery cuff together with radiation or chemotherapy. Ellen Jones, M.D., will study hyperthermia's effects on boosting tumor oxygen levels and in turn how increased oxygen enhances radiation's cancer-killing effects.

• Melanoma -- Douglas Tyler, M.D., will test whether heat treatment increases the effectiveness of chemotherapy in a rare, aggressive form of melanoma of the arm or leg. The limb's circulation will be cut off from the rest of the body during treatment to shield the vital organs from high dose chemotherapy.