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radiation and to drugs. In addition, physiologic factors inherent in tumors, such as chaotic blood flow and increased acidity, make tumor cells particularly sensitive to hyperthermia. "So you have a complementation of the interaction, as well as the heat sensitizing cells to these agents," said Leeper.
According to six randomized clinical trials, the net effect of this complementation and sensitization is a demonstrated benefit for patients who receive hyperthermia plus radiation over radiation alone for head and neck cancers, melanoma, breast cancer, brain gliomas, and tumors of the cervix and bladder. "The addition of hyperthermia to the standard course of radiation therapy in most of these studies has approximately doubled the response rate and doubled the local control rate; that is, freedom from cancer at three to five years out," said Leeper. "And three studies have also shown an improvement in survival."
Yet despite the proven benefit of hyperthermia, its use as an adjunctive therapy for cancer remains limited for several reasons. First, treatments
are lengthy, labor intensive, and expensive. And an even greater problem has been the lack of a good noninvasive thermometry system that would allow physicians to know exactly where and how much heat is being delivered. This has been especially problematic with tumors that are not near the surface, for instance in the cervix or colon. Leeper said that in the past two years, researchers have made significant advances in this area by using MRI to image temperature. "It's a technology that we're just about ready to apply."
Hyperthermia is also being investigated as an adjunct to gene therapy, he added, using genes that confer sensitivity to heat to regulate the expression of other genes that might have therapeutic effects, for example, toxins or immunomodulators.
Another new area of cancer research  that has generated great excitement in recent years and that may be used in conjunction with radiotherapy is the use of angiogenesis inhibitors. These are drugs that block the proliferation of new blood vessels, a process known as angiogenesis (see graphic above). In order for tumors
to grow, they require new blood vessels to deliver oxygen and nutrients. By blocking the formation of new vessels, researchers believe they may be able to starve the tumor. Since angiogenesis inhibitors are cytostatic (preventing the growth of a tumor) rather than cytotoxic (killing the tumor), they will most likely be used in conjunction with chemotherapy or radiation therapy as a cancer treatment.
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One of the anti-angiogenesis agents being tested at Jefferson is thalidomide, the same drug that was widely given, with disastrous results, to pregnant women in the 1950s as a treatment for morning sickness. Thalidomide was withdrawn from the market when it was shown to cause severe birth defects. But in 1994, researchers demonstrated that the very properties that damaged the developing fetus, that is, inhibition of new vessel growth, could be used therapeutically to starve tissues such as tumors. An RTOG-sponsored clinical trial of thalidomide used in conjunction with radiotherapy as a treatment for brain glioma is now underway (see article at left), with Jefferson's Adam Dicker chairing the correlative studies section of the trial.
Dicker explained that angiogenesis, as measured by the density of microvessels (the MVD) in a given area, has been shown in many
studies to correlate with tumor extent, aggressiveness, decreased survival, and lymph node metastases. A landmark paper in 1991 showed that in a study of women with breast cancer, all patients with microvessel counts over a certain threshold developed metastases. "This was the precedent for thinking, well, if there's increased angiogenesis in patients with more advanced disease, then presumably if you impact on the angiogenesis you might impact on the overall progression of the disease," said Dicker, who is collaborating on research with
George Iliakis, Ph.D., Professor and Director of the Radiobiology Division.
Another reason for the excitement about angiogenesis inhibitors is that preclinical data indicates little likelihood that tumors will develop resistance to these agents. "It takes a long time for these
anti-angiogenesis agents to have an effect," Dicker notes, "but they have a very durable length of response.
While Curran and the faculty in Radiation Oncology are proud of the basic, translational, and clinical research programs, Curran stresses that patient care is the top priority. To this end, the Kimmel Cancer Center recently celebrated the addition of two new partners, the radiation oncology center at Frankford Hospital, and the Jefferson radiation oncology center at Riddle Memorial Hospital in Delaware County. These facilities will help increase the number of newly referred patients seen through the Jefferson system to about 3,500 per year. Many of these patients are seen in multidisciplinary programs and benefit from the collaborations of researchers and clinicians in multiple specialties.
"We're devoted to offering state of the art therapy while at the same time critically evaluating its potential benefit to patients," said Curran. "Just because it's new technology doesn't mean it's better."
LisaJ. Bain
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