New Developments in Radiotherapy
Expand Cancer Treatment Options

The pace of development in radiation oncology is ever quickening as new concepts in dynamic tracking systems, molecular targeting, stereotactic targeting and treatment delivery, radiation sensitizing chemotherapy, and other innovations are being studied and put into clinical practice. The following represent technological advances currently in use at UT Southwestern, with each modality continuing to spin-off new ideas for future cancer treatment.

• RADIOSENSITIZING CHEMOTHERAPY
Combining chemotherapeutic drugs with radiotherapy has a firm biologic rationale. Such agents reduce the number of cells in tumors undergoing radiotherapy by their independent cytotoxic action and by rendering tumor cells more susceptible to killing by ionizing radiation. Many drugs are chosen for combination with radiotherapy based on their known clinical activity in particular disease sites. Alternatively, agents that are effective in overcoming resistance mechanisms associated with radiotherapy can be chosen. A number of potent chemotherapeutic agents, including taxanes, nucleotide analogs, and topoisomerase inhibitors have entered clinical trials or practice. Preclinical testing has shown that these drugs are potent enhancers of radiation response and thus might further improve the therapeutic outcome of chemoradiotherapy. Also, there are rapidly emerging molecular targeting strategies aimed at improving the efficacy of chemoradiotherapy.  Although we have made significant progress in our understanding of the role of combined modality therapy, much remains to be accomplished. Current and future research may provide exciting opportunities to improve response and survival for patients with tumors previously associated with a dismal prognosis.

• IMAGE GUIDED RADIATION THERAPY
Plain radiographs and even CT, PET, or MRI scans have been used for many years to help plan radiotherapy treatment delivery. While these tools have helped visualize tumor-bearing areas and their relationship to important normal structures, their implementation has been limited to mostly the planning process. Uncertainties in position of tumor and normal anatomy still have required that rather large safety margins around the tumors be used to avoid missing tumor targets. This problem results from the known anatomical movements that occur in any patient as a result of repositioning and natural processes including digestion and breathing. In the end, the disconnect between imaging for radiotherapy planning and delivery has limited the precesion and accuracy of radiotherapy delivery.

Two innovations have addressed these problems leading to dramatic improvements in the precision of radiation delivery: 1) stereotactic targeting and radiation delivery, and 2) dynamic image guidance. Together, these innovations and their implementation constitute an Image Guided Radiation Therapy (IGRT) program.

Stereotactic localization simply means to be guided toward a target by a “fiducial.” A fiducial is something that can be trusted and is generally a radio-opaque marker capable of being identified by several imaging platforms. In the end, a fiducial is used to create a mathematical coordinate system identifying the positions of targets, normal tissues, and instruments for treatment delivery in three dimensions. Still, the concepts of stereotactic radiation delivery go much beyond these definitions of stereotaxy itself. Stereotactic treatments constitute a formalism whereby the entire treatment process is more sophisticated, more accurate, and delivered with greater care than a conventional radiotherapy treatment. This attention is justified given the dramatically higher doses of radiation given in one or very few treatments. Such treatments are much more biologically potent than conventional radiation both to intended tumor targets and also to any normal tissue innocently exposed.

Stereotactic radiosurgery is a non-invasive treatment in which high doses of radiation beams are delivered to a tumor in a concentrated, precise manner. With stereotactic radiosurgery, many beams of radiation are utilized (often more than 100) coming from different directions. Each of these many beams is relatively weak and therefore causes minimal entry damage. However, when all the beams converge at the target, their cumulative effect adds up to an extremely potent dose aimed at destroying the target cells with great precision. Typically a single, high-dose application of radiation is delivered to a tumor instead of the many smaller doses given in standard radiation treatment.

Stereotactic radiosurgery was originally developed for treating central nervous system (CNS) problems including brain tumors, vascular malformations, and certain neurological functional disorders. Clinicians from UT Southwestern have extensive experience in treating these problems with both the CyberKnife® and Gamma Knife treatment platforms.

The CyberKnife® stereotactic radiosurgery system includes tracking software that can carry out radiosurgery for lesions anywhere in the body CyberKnife® consists of a compact linear accelerator mounted on a robotic manipulator arm, coupled with two orthogonal X-ray imaging cameras that allow for tracking of the tumor target. This technology is image-guided and allows discrete areas in the brain or body identified as tumor to be treated with significantly higher doses while sparing normal tissue.

The soon-to-be installed Gamma Knife radiosurgery system at UT Southwestern University Hospital-Zale Lipshy uses 201 separate beams of Cobalt-60 irradiation to target abnormal tissues. While limited to just brain disorders, the Gamma Knife is extremely precise and well suited to both common tumor disorders as well as more uncommon functional disorders like trigeminal neuralgia. The Gamma Knife™ is capable of extremely conformal radiation delivery, making it particularly suited for complex shaped skull-based tumors such as meningioma as well as vascular problems such as arteriovenous malformations.

Stereotactic Body Radiation Therapy (SBRT) is the natural extension of the principles and successes seen from CNS radiosurgery. Localized tumors in the body can be targeted and treated using stereotactic techniques in a similar fashion as with the brain so long as motion is accounted for appropriately. In the brain, motion is not a significant problem using rigid halos or tight fitting masks. In the body, however, tumors move constantly by natural processes such as breathing, causing significant problems with accuracy. Nonetheless, clinicians and physicists from UT Southwestern have led the development of SBRT through innovation and clinical testing.

At UT Southwestern, three platforms are used for SBRT including the Accuray Cyberknife®, the Varian linear accelerators in the Dallas Moncrief center, and the soon to be installed Elekta Synergy-S® image guided system. All of these systems are used in conjunction with the Elekta Stereotactic Body Frame® as a means to effectively immobilize patients and decrease respiratory motion. The use of SBRT in several sites has been shown via clinical testing to be an exciting non-invasive therapy capable of eradicating tumors with acceptable complications. Researchers at UT Southwestern continue to push the envelope of prudent use of SBRT by formally testing the therapy in national trials, sponsoring international educational symposia to discuss results and research, developing the most modern technologies to carry out SBRT, and investigating biological correlates that may ultimately allow better understanding of the therapy and guide its proper use.

Dynamic Image Guidance is facilitated by systems that locate tumor or normal tissues on a real time or near real time basis. As such, much greater confidence in targeting accuracy is realized allowing further shrinking of safety margins for stereotactic radiation delivery. In the end, such systems translate into extremely accurate non-invasive focused radiation delivery with decreased collateral injury to surrounding normal tissues. The department will soon install the Elekta Synergy-S® image guided linear accelerator at the Dallas Moncrief center. The Synergy-S® platform allows for a cone-beam CT scan to be carried out on the treatment table immediately before radiation delivery. As such, adjustments can be made to insure that the planning process is coupled as closely as possible to the delivery of treatment. Both tumor tissue and surrounding normal tissues can be identified on these high resolution CT images facilitating the most accurate treatment possible.

The Synergy-S® system, as well as the Cyberknife® platform, are ideal instruments for SBRT given their accuracy and capabilities to deal with tumor targeting and normal tissue avoidance. In turn, the Gamma Knife constitutes the ultimate in accuracy for CNS lesions and is complimented by the versatility of the Cyberknife® for treating brain disorders. Still, despite being the only center in North America with all three of these platforms, the true value of UT Southwestern’s image guided stereotactic program is the experience and expertise of the treatment team including the physicians, physicists, dosimetrists, nurses, therapists, and other treatment personnel.

• INTENSITY-MODULATED RADIATION THERAPY 
In the 1980’s 3-D conformal radiotherapy allowed tumors to be visualized in multiple directions to facilitate radiation delivery from any direction. In addition, each of the many beams’ apertures could be shaped precisely like the tumor target to create dose outlines conforming to the tumor. A more recent advance, Intensity-Modulated Radiation Therapy (IMRT) is a special type of conformal external beam radiation in which the strength of any beam varies across its aperture allowing the most potent delivery to the tumor while sparing the same damaging dose to nearby normal tissues. IMRT allows safer delivery of higher than conventional doses of radiation. It allows the radiation to treat an area that is shaped like the tumor and to penetrate as deeply as the tumor is located. By treating this way, the dose of radiation to the healthy areas near the tumor is minimized, and the dose to the tumor is maximized. With IMRT, doses higher than the standard dose of radiation therapy may be delivered to better control cancer without increased toxicity.

• BRACHYTHERAPY
Brachytherapy is internal radiation therapy using an implant of radioactive material sealed in needles, seeds, wires, or catheters placed directly into (interstitial implant) or near a tumor (intracavitary therapy). Thus, the radiation is emitted outward through the affected area rather than from an external source across normal tissue. Depending on the individual case, brachytherapy may be given with low-dose sources where treatment may take place over several days in the hospital or with a high-dose rate (HDR) device that allows for treatment in minutes on an outpatient basis. High-dose rate brachytherapy is usually given in two to three outpatient visits. A device or holder is placed into the organ to be treated. The device is then connected to the HDR machine and a small but intense radiation source is loaded into it. The dose is delivered in approximately 5 to 10 minutes. Once the treatment session is complete, the radiation source is withdrawn back into the machine and the device is removed from the organ being treated. The patient is discharged to return a week or two later for additional treatments. Currently brachytherapy is being used to treat breast cancer, head and neck cancer, gynecological cancer, and prostate cancer.

• CONCLUSION
The above treatment approaches represent the leading edge of Radiation Oncology. Innovative and conventional clinical applications of these technologies are being utilized at UT Southwestern to provide patients with the latest advances while ensuring their safety.