implement it," said Galvin. But in the early '90s, he and others introduced a new field-shaping device called the multi-leaf collimator, with which one can obtain any irregularly shaped field using a computer to drive fingers in and out of the radiation beam. "It occurred to me that if you shaped different fields and then stacked them up, you could build up any intensity pattern. So with the introduction of the multi-leaf collimator, we now had a tool to modulate the intensity of the beam so we could deliver these inverse plans."

This allowed radiation treatments to be shaped to irregular tumor volumes. "We could now shape the dose to a horseshoe-shaped tumor with a critical structure right in the center of it. We couldn't do that in the past."

The problem with inverse planning is that the computer sometimes comes up with very elaborate solutions: elegant dose distributions that are difficult to deliver because of various compromises that were called for during the planning process. For example, when the tumor surrounds a critical structure, the delivery of sophisticated distributions of radiation sometimes requires sacrificing dose homogeneity.

"So here at Jefferson we asked, well, if we're going to change the rules of treatment planning so dramatically, then why not go back to the traditional techniques and see how they perform under this new set of rules," said Galvin. This has led to the development of a new approach, dubbed forward planning as opposed to inverse planning. "We still have made it an intensity modulated delivery, it's just that whereas we had inverse planning coupled with IMRT, we're now using traditional techniques combined with IMRT. We have fields within fields and we still stack fields, but we use our past experience to say what those fields within fields should look like." While optimization of the plan is still left to the computer, said Galvin, "We give the computer more information going in, and tell the computer that we think that these fields are the ones it should be looking at. 'Now, computer, you optimize it.'"

Galvin explained that while inverse planning may be the wave of the future, the forward planning technique being developed at Jefferson is more suited to the technology that is currently available. Eventually, there may be a melding of the two approaches, he said. "The terminology will change-it will become simply computerized planning."

Holding Still

Another device that maximizes delivery of radiation to the target and not to surrounding tissue is the stereotactic body frame (see adjacent photo), a piece of equipment with calibrating devices built into it that allow the precise localization of body structures in three dimensions during a CT or MRI scan. Historically, patients simply lay on a table while receiving radiation therapy. Then, plastic molds were introduced which kept people from rolling around during treatment. "But if you want to give high doses of radiation to critical areas in the body, we've concluded that you really need to have more rigid immobilization," said Curran. Jefferson was one of the first American sites to use the stereotactic body frame to immobilize patients during radiation therapy, and remains the only one in the Delaware Valley.

The device looks barbaric, Curran remarks, resembling the kind of box a magician uses when he cuts a woman in half. The patient is placed in it prior to a CT scan. Images produced from this scan show the location of the tumor relative to fixed points in space provided by the calibrating device. Then, while the patient's positioning is maintained by the box, he is moved to the treatment area where radiation is delivered relative to those same fixed calibration points.

The difficulty comes in transferring the patient from the CT scanner to the treatment area. Jefferson staff, however, have developed a unique transferring technique in which the patient can be moved off the CT scanner, down the hall, and into the treatment unit without being jostled.

The Jefferson team uses a modified hospital gurney to facilitate this transfer. The gurney allows the staff to slide the patient smoothly off the CT couch, onto the transfer couch, and then onto the treatment table. Then, using marks on the patient and on the frame, the radiation fields are delivered to an exact position within the patient's body.

"The importance of doing this is that we can now decrease the margins," Galvin explained. Margins refer to the area surrounding the tumor that may be irradiated during the treatment. Less precise localization of the tumor or more uncertainty about the patient's exact position relative to the images means that those margins must be increased in order to ensure adequate delivery of radiation to the tumor. "We're trying to minimize the size of the margins so that we are irradiating less of the healthy tissue, while still getting all of the tumor."

New Approaches Make Radiotherapy Better

For all of these new technologies, rigorous evaluation of the results is the key to ensuring progress in the search for better treatments. Jefferson patients benefit from participation in clinical trials of protocols developed all over the world, due to the university's involvement in federally funded cooperative oncology groups such as the Radiation Therapy Oncology Group, which Curran currently chairs. These clinical trials are essential for the continued evolution of therapies that will yield better outcomes and fewer side effects.

For example, clinical trials recently resulted in preliminary FDA approval for an agent called amifostine, which protects against radiation-induced dry mouth, or xerostomia. Werner-Wasik with Robert Capizzi, M.D., the Magee Chair of the Department of Medicine, conducted this trial at Jefferson, and Werner-Wasik continues to see if this agent might be useful as a protectant against chemo- and radiation-induced esophagitis in lung cancer patients.

Adam Dicker, M.D., Ph.D, Assistant Professor of Radiation Oncology, meanwhile has been working with a technique called brachytherapy, in which radioactive seeds are implanted into early stage prostate tumors. Dicker collaborates with Professor Frank M. Waterman, Ph.D. The idea behind brachytherapy is that higher doses of radiation can be delivered directly to the tumor, without affecting adjacent tissues. Long term studies of the effectiveness of brachytherapy are underway, as is research to improve the methodology.

Adjuvant Therapies

Many of the most promising developments in radiation oncology involve the use of adjunctive therapies that augment the standard treatment. One that has undergone extensive development at Jefferson is hyperthermia, or applying heat to the tumor. In the past two decades, said Dennis Leeper, Ph.D., Professor of Radiation Oncology, about 700 patients have received hyperthermia treatments at Jefferson.

Hyperthermia increases the effectiveness of radiation therapy through two pathways: by killing cells directly and by making cells more sensitive to radiation-induced damage. The mechanisms of hyperthermia's effects are biochemically quite different from those of radiation and drugs, Leeper explained. First, heat denaturizes proteins, in the same way that when you cook an egg, the protein in the white changes from a clear, slippery liquid to a white solid mass. By denaturing and changing the structure of proteins in cells, heat inhibits the repair of the tumor's damage from radiation and chemotherapeutic agents.

Second, through other chemical and biochemical processes, heat makes the tumor's DNA more reactive with drugs and radiation, increasing the effectiveness of the drugs and radiation. And what makes the combination of heat and radio-or chemotherapy even more desirable, is that the cells in tumors that are sensitive to heat are resistant to

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