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June 21, 2004

Ready, Aim (Carefully), Fire: Radiation Therapy and Radiosurgery Can Hit Increasingly Challenging Targets
By Jim Knaub
Radiology Today

Smaller lesions. Tumors near the brain stem and other sensitive structures. Even moving targets such as lung cancer lesions are what researchers and clinicians are aiming for—while minimizing irradiation of surrounding tissue.

If cancer patients and their tumors were two dimensional, radiation therapy and radiosurgery would be a snap. Immobilize the patient, adjust the collimator on the linear accelerator so it matches the tumor size and shape, and blast away.

“Radiation can kill any tumor with enough dose,” says Scott Johnson, PhD, product manager with Varian Medical Systems, a manufacturer of oncology equipment.

But in a 3-D world, tumors are surrounded on all sides by healthy tissue, sometimes right next to vital structures. They can even present a moving target, shifting as the patient breathes. Throw in the fourth dimension—tumors grow over time or recede with treatment—and you have the challenges facing healthcare teams using radiation therapy or radiosurgery to treat cancer. The difference between radiosurgery and radiation therapy (or radiotherapy) is that radiosurgery is planned as a single, one-time procedure while radiation therapy consists of a planned series of procedures.

Tighter Margins
Researchers are working to improve targeting so clinicians can minimize the area of healthy tissue treated around the margins of tumors and to treat tumors next to delicate structures such as the optic nerve. Howard Maccabee, MD, PhD, explains that advancements in radiosurgery and radiotherapy come from the coalescing of four key technologies in the past 20 years:
1. Computer capacity. Handling the large amounts of data and making the rapid calculations needed for radiation therapy and radiosurgery requires high-speed computers. “Everything is happening all at one time,” says Maccabee, a radiation oncologist at John Muir Medical Center in Walnut Creek, Calif. “The multileaf collimators are shifting and the gantry is moving all at one time. You can also change the intensity of the radiation for IMRT [intensity modulated radiation therapy]. All this is only possible with a modern computer-driven system.”
2. Modern imaging. In various radiation oncology systems, CT, MRI, PET, x-ray, or ultrasound all provide images to the computers used to calculate treatment plans.
Novalis’ Shaped Beam radiosurgery system, one system Maccabee works with, uses both CT and MRI images to calculate treatment plans. “You can see the bony anatomy better with the CT scan, but you can see the lesion anatomy better with the MRI,” Maccabee says, “so by fusing both images on the computer, you have the ability to do radiosurgery.”
3. Patient fixation. Modern technology can achieve accuracy to within 1 millimeter, but such accuracy isn’t much good if you can’t immobilize the patient’s treatment area. Immobilization techniques developed for neurosurgery make precise radiosurgery possible and have also been adapted for use in radiotherapy.
4. Targeting technology. Stereotactic surgery techniques and other targeting technology provide the accuracy to irradiate tumors adjacent to anatomic structures with low tolerance to radiation, such as the spinal cord. Advancing targeting technology to treat tumors in locations that can’t be completely immobilized is a challenge still facing researchers.

Shoulders of Giants
Those technologies in combination have helped make IMRT, image guided radiation therapy (IGRT), and stereotactic radiosurgery and radiotherapy state-of-the-art tools for treating cancer with radiation. And those tools are evolving in what Maccabee calls “building on the shoulders of giants.”

For example, IMRT was first widely used to treat prostate cancer, Johnson says, but is now showing promise in treating head and neck cancers. “With head and neck cancer, the tumors tend to be large and there’s a lot of normal surrounding anatomy,” Johnson says, explaining that radiation therapy in head and neck cancer must treat around vital structures such as the brain stem, larynx, eyes, and optic nerves.

The May issue of the International Journal of Radiation Oncology • Biology • Physics reported promising results on IMRT for treating 74 patients with head and neck cancers, most of which were treated when the cancer had reached an advanced stage.
“After being treated with IMRT, the estimated four-year survival of all patients was 87%,” according to the American Society for Therapeutic Radiology and Oncology. “Eighty-one percent of those patients were estimated to be completely disease-free after completing treatment. If patients had surgery to remove the tumor in addition to being treated with IMRT, the chances of survival rose dramatically to 92%. Without surgery, 66% of the patients survived.

“This is the largest IMRT study in patients with oropharyngeal cancer, and the results are very promising,” says K.S. Clifford Chao, MD, the lead author of “Intensity Modulated Radiation Therapy for Oropharyngeal Carcinoma: Impact of Tumor Volume.”
Novalis’ Shaped Beam Surgery, a stereotactic technique for radiosurgery and radiotherapy, may have some overlapping applications with IMRT but is designed to treat tumors and lesions as small as 1 centimeter with accuracy to within 1 millimeter. Both systems use multileaf collimators—a series of movable leaves that can shift position to manipulate the beam into almost any desirable shape.

Head and Neck IMRT
“IMRT is already developing nicely with respect to head and neck cancers; we haven’t proven any superiority for the stereotactic technique,” Maccabee says, “but there are cases we might be able to treat that IMRT might not.”

He mentioned a recent patient with a small tumor in his sinus cavity positioned directly behind his nose, between the eyes, and near the pituitary gland. Maccabee says the stereotactic approach might be a better option in this roughly 1-centimeter space. In his experience, IMRT is typically better for lesions 4 centimeters or larger. The stereotactic radiosurgery system can treat tumors of any size and shape up to 10 centimeters square. He notes that IMRT has the advantage of treating even larger tumors without breaking the procedure into sections.

“The Shaped Beam system can’t treat giant tumors, but with giant tumors, you don’t need the exquisite shaping capability that you need for small lesions in the brain or elsewhere in the body,” Maccabee says. He thinks the Novalis system will prove valuable for treating small tumors previously considered inoperable.

“There are many brain lesions which are either not operable or not resectable, meaning the danger of cutting something out would be greater than the potential gain in terms of health or neurological status,” Maccabee says. “We can hit any area of the brain. This is a godsend to neurosurgeons who had to turn away patients who had tumors they could almost operate on, but not quite. Most of those cases can now be treated with stereotactic radiosurgery, without the risks of surgery.”

Maccabee and colleagues Terrence Chen, MD; Geoff Ady, MD; Vincent Massullo, MD; Dan Chinn, MD; Ram Virudachalam, PhD; and Quing Lei, MD, have treated 40 to 50 patients with the Novalis Shaped Beam System—predominantly with head and neck cancers. Other researchers are evaluating the new system for treating other areas of the body, including tumors located in and around the spine.

Sensitive Surroundings
“Because we concentrate all this radiation on some small target in the body,” Maccabee says, “which is done automatically by the computer in these rotational techniques, it lowers the dose on the normal surrounding tissue. We can treat a lesion that’s right next to the spinal or the optic nerve that was not possible before because you would exceed the radiation tolerance of those structures. By shaping the beam and using the rotational treatment plans, you can give a dose that’s enough to control the lesion without damaging the sensitive structure such as the brain stem or the optic apparatus. The target can get 100 times the dose of the normal tissue.”

Another stereotactic radiosurgery system, Accuray’s CyberKnife, is being investigated for treating local tumors in patients with pancreatic cancer. Both CyberKnife and Novalis’ systems are indirect descendants of the Gamma Knife system developed in the 1960s and still widely used. Elekta’s Gamma Knife utilizes a series of interchangeable round collimators instead of an adjustable multileaf. Novalis Shaped Beam works with a standard linear accelerator. The CyberKnife is manipulated by a robotic arm.

Results from 15 patients treated with the CyberKnife at Stanford University Medical Center were recently published in the International Journal of Radiation Oncology • Biology • Physics. The study evaluated different radiation doses to determine how much radiation was needed to stop the growth of pancreatic tumors in patients whose tumors were considered inoperable with traditional surgery. The researchers found that all seven patients who received a 25-gray dose either showed no tumor growth or had their tumors reduced by treatment.

“The importance of this study is that it establishes a promising role for CyberKnife radiosurgery in the treatment of locally advanced pancreatic cancer,” says Albert Koong, assistant professor of radiation oncology at Stanford Medical Center. “The future challenge is to determine the most effective way to incorporate this treatment with other therapeutic strategies.”

Pancreatic Cancer
Koong points out that local tumor control is only one clinical end point for pancreatic cancer, an extremely lethal disease with a high rate of metastasis to other areas of the body. “Our next trial, currently underway, combines a CyberKnife radiosurgical boost treatment with standard chemotherapy and radiotherapy to treat the systemic spread of the disease, in addition to local control of the pancreatic tumor.”

While patient fixation techniques permit great accuracy, much of that accuracy disappears if the tumor is located in a part of the body that can’t be readily immobilized. To solve that, researchers are working on systems that track tumors such as lung cancers and others in the chest cavity that will always present a moving target. Varian’s Johnson says accounting for patient motion will be a key breakthrough in broadening IMRT’s applications.

Some systems now use implanted markers to verify when moving tumors, such as prostate tumors, are properly aligned with the treatment field and pulse the beam accordingly. The next generation may prove to be systems that can track and treat the tumor target as it moves.

“A year-and-a-half or two years from now, we may be using imaging systems to monitor respiration in real time and correct for respiratory motion,” Johnson says. “To monitor respiratory motion and compensate in real time is important for treating everything between the shoulders and the pelvis. Once in wide use, it would greatly reduce the amount of normal tissue that gets irradiated.”

Varian’s and other companies’ work in this area takes advantage of a range of techniques lumped into a group called IGRT. These technologies use different approaches, but all have some imaging method integrated into the system to calculate or double-check the treatment plan. For example, Siemens’ Primatom integrates the company’s Primus linear accelerator with a Somatom CT scanner. North American Scientific’s BAT (B-mode Acquisition and Targeting) systems use ultrasound to image tumors in the abdomen. Originally developed for use in treating prostate cancer, BAT applications have expanded to include bladder, breast, cervix, pancreas, and liver treatment.

Varian, as well as other companies, uses electronic portal imaging techniques to double-check treatment plans to account for changes that occur over the course of a series of treatments. Johnson says Varian is working on a system that uses a kilovoltage x-ray source that produces a high-quality, low-dose image. Immediately before each treatment, the patient is positioned and two reference images are taken. Those images are compared with the reference scan to see whether or not the treatment needs to be adjusted slightly—usually less then 1 millimeter or 1°, according to Johnson.

Looking Ahead
So where is it all headed? Johnson believes a tracking system that accounts for patient motion is a key advancement for continued progress in IMRT, especially for lung cancer and other tumors in the abdomen and chest cavity.

Maccabee sees fantastic possibilities as MRI provides ever greater detail and stereotactic techniques provide the ability to accurately hit such a small target.

“We have some science-fiction–type dreams on using radiosurgery techniques on lesions that cause other types of diseases such as Parkinsonism and certain psychiatric conditions,” Maccabee says. “People are using MRI to look at everything now and finding all kinds of things that they never expected to find. Eventually, those findings will become targets. Someday we may be able to treat some unusual psychiatric diseases with radiosurgery. But that is a question mark for the future.”

— Jim Knaub is editor of Radiology Today.

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