Radiation Therapy’s Aim … Is True

A blended CT and PET image shows a cross-section of the head in the nasal cavity area. This image was co-registered using Varian Medical Systems’ Eclipse treatment planning software. The white cross hairs come together at the tumor site. The lines around the tumor are part of an IMRT treatment plan and show that the highest radiation dose is being concentrated right in the tumor, with the dose falling off rapidly as you move away from the tumor. This plan was designed for maximum preservation of the brain stem, which, in this case, is avoided altogether.

From the beginning, radiation therapy’s objective has generally focused on limiting radiation exposure to healthy tissue while delivering a lethal dose to the cancer. The concept is simple; the practice is anything but.

To gauge the headway made in the field, consider an exam on a patient with prostate cancer circa 1980. After filling the patient’s colon and bladder with contrast, a technologist took supine and lateral radiographs of the area. Rather than the prostate, however, the films showed only the enhanced neighboring structures, leaving the radiation oncologist to guess the relative position of the gland. A planning treatment volume was set?ever liberally?and the diseased area, rectum, and bladder were radiated with near-equal measure.

A chief refinement in the localization process occurred when sophisticated computers entered the planning stages, and 3-D conformal therapy was born. The procedure, widely used today, uses CT- and often MR-based cross-sectional data in the plan, allowing the radiation oncologist to define both the tumor target and the normal structures in three dimensions, according to Najeeb Mohideen, MD, clinical director of radiation oncology at Loyola University (Maywood, Ill). The therapy employs multiple beams that enter the body from various angles and converge on the tumor target. Using a multi-leaf collimator, a dosimetrist shapes these beams to the tumor’s 3-D contour.

CBCT fused with planning CT with IMRT plan isodose overlay.

Mohideen notes that 3-D conformal therapy offers the ability to quantify exposure levels. “The treatment-planning system has evolved to show us the dose distributions all throughout the tumor in three dimensions, and also the dose flash on the normal structures,” he adds. “This helps us to better plan the treatment and spare normal tissues while not losing any coverage of the target. The system marks a huge leap forward from everything that was done previously in the field in a two-dimensional mode.”

The ability to precisely locate and direct therapeutic beams at a tumor target, however, does not always translate into the ability to avoid healthy tissue. Tumors can sit adjacent to or wrap around organs that are highly sensitive to radiation, such as the optic nerve and the spinal cord. The flat beams of radiation associated with 3-D conformal therapy, regardless of how they are shaped, have no chance of hitting a U-shaped tumor without bombarding the structure amid it, Mohideen explains.

A Difference in Intensity

In the late 1990s, a system called intensity-modulated radiation therapy (IMRT), an offshoot of 3-D conformal therapy, addressed this issue by primarily focusing on the quality of the therapeutic beams. Instead of 3-D’s uniform beam, IMRT’s beamlets?which vary in intensity from low to high dosage?allow the physician to paint a much tighter dose around the target, sparing healthy tissue to a far greater degree, according to Mohideen.

“For example, say the target is the tongue and lymph nodes on either side of the neck,” he explains. “Since we have the spinal cord running down the middle of the vertebral column, if the dose is not shaped like an island around the spinal cord, the cord can receive the same dose as the neck or the base of the tongue. This potentially can cause spinal cord damage. [With IMRT,] the physician is able to vary the intensity of the beam, achieving the desired dose coverage while keeping within the tolerance of the spinal cord and other critical structures.”

According to Tim Williams, MD, radiation oncologist for Lynn Regional Cancer Center (Boca Raton, Fla), “[IMRT] is a very complex therapy. It takes a lot of time to calculate the doses and to verify them on the machine, so the treatments take longer.” Williams walks through the planning stages of a typical IMRT procedure for a prostate tumor: The technologist initially opacifies the patient’s bladder and urethra, and then acquires a thin-slice CT scan through the pelvis for a primary data set. An MRI scan provides a secondary data set. Reference points are marked on the patient amid the scans.

Everything else prior to the radiation treatment is performed on the computer in the patient’s absence, Williams explains. The data sets are downloaded and fused in the treatment-planning computer, which help determine the beam geometry. Physicians manually map out target volumes and identify the essential parts of the anatomy that the beam should hit or avoid. “Once you provide the computer with your beam angles and target volumes, it will calculate a dose profile that will provide a specified dose to the tumor while protecting normal adjacent structures,” he says.

Williams notes that IMRT procedures as well as 3-D conformal therapy use radiation doses that are fractionalized?generally spread out over 5?8 weeks?to allow reparation of healthy tissue. The practice revolves around a critical fact of radiation biology: Cancer cells do not repair radiation damage as efficiently as normal cells. Unfortunately, the logistics involved in accurately replicating the required number of IMRT exams can cause difficulty in some situations, he adds.

Mohideen concurs, adding, “Immobilization of the patient is much more stringent with IMRT. Because of the intensity modulation, movement and setup errors, as well as organ changes, make the exam much more difficult to reproduce on a daily basis. Such factors make IMRT less optimal for lesions like lung tumors without correcting for respiratory movements and shape distortions during the respiratory cycle.”

The Art of Targeting

Surface dose rendering shown on a model view of an IMRT plan for base of tongue tumor.

These issues illustrate yet another challenge that field experts face in the quest to spare normal tissue from exposure during therapy?the fact that the body’s dynamism can cause a tumor to be either set in motion due to respiration or displaced from an earlier location. This reality prompted last year’s introduction of image-guided radiation therapy (IGRT), designed to further hone targeting methods.

Unlike previous systems, IGRT?which could incorporate a modulated beam?fine-tunes the localization process by allowing image acquisition of the patient at the time of treatment, says Scott Johnson, manager of research collaborations at Varian Medical Systems (Palo Alto, Calif). Physicians then compare these images to the reference images acquired in the planning stage to ensure that the therapy beams are indeed on target.

“IGRT increases the accuracy of the delivery,” Johnson says. “For example, if a patient needs 35 fractions, you can deliver them with more confidence knowing that the tumor is properly positioned, because you’ve acquired images and analyzed them directly before turning on the beam. Without the confidence [that daily imaging provides], you have to expand the target volume in three dimensions to account for the uncertainty in the positioning that day.”

Three types of target volumes are applicable to radiation therapy, according to Mohideen. “The gross target volume [GTV] is the area that is clinically abnormal. The clinical target volume [CTV] expands to include the area that, although not clinically abnormal, is likely to be involved with microscopic disease. The planning target volume [PTV] further expands to account for day-to-day movement, setup error, and organ motion.” With IGRT, physicians can adjust the PTV to the CTV without fear of leaving disease areas untreated.

Varian’s On-Board Imager IGRT system, among others, currently uses radiographs or CT scans to check localization at any point in the therapeutic procedure, according to Johnson. X-rays, taken at 90? angles, generally are used for tumors in the head and neck region, where skeletal landmarks can indicate placement of relatively fixed targets. X-rays also can be used to check localization for drifting areas like the prostate; however, in these cases, radiopaque seeds must be implanted in the target. Otherwise, CT slices are taken to visualize the soft-tissue anatomy in question.

Machines by Varian, among others, currently handle tumors affected by respiratory motion by way of 4-D gating procedures, whereas the beam is controlled by an infrared camera monitoring upper and lower thresholds of a block that rests on the patient’s chest, Johnson explains. The therapy beam stays on during respiratory expiration only, so the tumor target remains somewhat consistent.

Stereo Radio

PET Hybrids: Seeing Beyond the Naked Eye Although CT and MR are mainstays in the planning stages of radiation therapy, the PET/CT hybrid scanner currently is not. But this might not be the case for long. PET scans indicate hot spots of a glucose-based tracer that, upon injection, heads straight to metabolically active areas like cancerous tissue. The low-level background that traditional PET scans provide, however, can cause difficulty in localizing the area, according to David Rollo, MD, PhD, chief medical officer for Philips Medical Systems (Milpitas, Calif). Five years ago, a PET/CT hybrid was introduced to address this and other shortcomings of standalone PET. The latest hybrid combines the newest technology of both modalities, and the result is a machine that is extremely effective at determining the full presence of cancer, Rollo notes. “The metabolic information of PET, combined with the anatomic information that CT provides, has helped tremendously in increasing the accuracy and confidence of the physician,” he says. According to Najeeb Mohideen, MD, of Loyola University, “PET hybrids can help in so many ways. It has helped us in diagnoses, improving staging, and in determining whether the patient has a residual or recurrent tumor. With lymphomas, for example, we gain far more information when we use PET rather than just conventional CT scans, because PET shows whether there is active disease in normal-sized lymph nodes. If nodes are normal on CT and abnormal in PET, we will cover it in the treatment plan.” PET’s ability to gauge response to treatment is equally significant, Rollo adds. He notes that a post-radiation treatment scan with a hybrid machine can provide dramatic indications of a tumor’s improvement that might not be seen on strictly anatomically based images until up to 6 months later. Devoid of PET’s contribution, the physician could erroneously assume that the radiation treatment was ineffective. “There’s no question about it,” Mohideen says. “PET will play a much bigger role in radiation therapy in the future.” ?MD

Some tumors, like those in the head, are relatively devoid of motion and can be fixed with nearly no movement, says Samuel Hellman, MD, an AN Pritzker distinguished service professor for the department of radiation and cellular oncology at the University of Chicago. Small and solitary brain lesions can be treated with stereotactic radiosurgery, which borrows the same stabilization frame that neurosurgeons use for operations, and involves shooting a single mega-dose of radiation into the tumor. The goal, as with a surgical operation, is to destroy everything in the target volume. While some of the healthy tissue is radiated, only the tumor?poised in the intersection of the multidirectional beams?receives the hyper-volume, according to Hellman.

Although originally designed for the head, stereotactic radiotherapy is now being adapted to other areas of the body using conventional fractionation and relocatable frames that can be removed daily. “In certain areas, we’re now able to take advantage of the biologic effect of fractionation along with the precise accuracy of this system,” Hellman notes.

The precision afforded by IMRT, IGRT, and stereotactic methods is not always the goal in radiation therapy. “It depends on the structure you’re treating, the dose you’re trying to achieve, and the patient’s overall condition,” Williams explains. “A substantial part of our treatment is palliation, [that has] a moderate dose of radiation to alleviate some specific symptom like pain, obstruction, bleeding, [etc]. In these patients, precision is not necessary, because the dose isn’t risky, and the tumors are larger.

“There are other situations where IMRT [or other precision-oriented therapy] just hasn’t shown to have any significant value,” Williams continues. “For example, unencapsulated pancreatic tumors send little fingers into the surrounding tissue. If you get too precise with the planning, you’ll miss all of those microscopic extensions. Using modulation is only as good as the understanding of the oncologic and biologic aspects of the tumor.”

Therapy from Within

Internal radiation, or brachytherapy, is an alternate method of targeting radiation to the tumor that involves implanting radioisotopic seeds in a lesion, Hellman says. For the treatment of prostate cancer, permanent seeds that decay over time are inserted into the gland under ultrasound or MR guidance. For cancer of the cervix and uterus, and a number of head and neck tumors, removable seeds are implanted. The latter cases employ two methods: Radioactive seeds with a low dose rate are inserted for a few days, or high-dose seeds are deposited through an implanted receptacle for just a few minutes, according to Hellman.

While Hellman believes that in prostate cases, IMRT often causes less damage to surrounding tissue than brachytherapy, “they’re both acceptable treatments,” he says. “In these situations, there are advocates for both IMRT and brachytherapy. Surgery is another option?it often depends on which door you walk through.”

Hellman adds, “Treatments [for tumors in general] are based on established guidelines, but many cases are unique and can lean physicians one way or another. Increasingly, patients are treated with a combined-modality approach using surgery, radiation, and systemic adjuvant therapy like chemotherapy. Radiation is a method of destroying the tumor and curing it in the area you treat, similar to surgery. That approach is quite different from chemotherapy, which is given systemically and is especially effective against small amounts of disease widely spread.”

Mohideen notes, “The sequencing and scheduling of treatment decisions depend on the site of the tumor and the stage. In general, most cancer management is discussed in a multidisciplinary clinic, which includes the surgeon, radiation oncologist, and medical oncologist. [Treatment] often depends on the strength of the institution’s specialty. Head and neck cancer, for example, can be treated with surgery or with chemo and radiation. Our program has an excellent surgeon who performs many extensive resections followed up with postoperative radiotherapy; other institutions might opt for chemo and radiation in similar cases. But across the board, radiotherapy is used in about 60 percent of all cancer patients as either the primary treatment, postoperative treatment, chemo and radiation treatment, or preoperative treatment.”

Down the Road

As far as the future is concerned, experts have a wealth of areas to explore. “Exciting laboratory developments are using radiation-inducible genes,” Hellman says. “A harmless gene is introduced into the patient, which can be ?turned on’ like a switch with standard radiation therapy. When these genes are radiated, they kick in to help kill the tumor. Work also is being done with viruses that are benign unless they’re in a radiation field, whereupon they grow and kill cancerous cells.”

Williams says, “Compounds are being developed that will allow protection of normal areas. We’ll be treating patients who go through their course of radiation with molecules and drugs that both sensitize the tumor and protect the normal tissue.”

Hellman adds, “A proton beam has the advantage of stopping when it reaches the tumor, so doses of the normal tissues can be reduced. You still have the entrance doses, but not the exit doses.” According to Williams, only a few centers in the country currently have this technology. “They’ll find a place in pediatric tumors, tumors of the eye, and some other areas, but because of the expense of the centers, they will remain a niche application [in the foreseeable future],” he says.

Mohideen sees a rise in personalized medicine. “There’s an explosion of information coming from within the field of genomics and proteomics, and much of it presently has to do with which kind of patient is likely to benefit from certain treatments. For example, in breast cancer, oncotyping is now done to select patients who have a higher chance of failure and will likely benefit from adjuvant chemotherapy. Right now, that information is being used to prognosticate; these approaches might soon have an application in radiation therapy.”

Refinements are ahead in 4-D imaging, involving tracking tumors in motion, Varian’s Johnson says. “Currently with gating, the beam turns on and off to account for the moving target. With tracking, the beam stays on and moves to follow the moving target, shortening treatment times. That’s the next big step?real-time monitoring [using fluoroscopy] of internal anatomy during the treatment.”

“Adaptive therapy” also is in the works for Varian’s IGRT system, which seeks to narrow the target area midtreatment for shrinking tumors, Johnson says. In this scenario, the treatment plan adjusts daily to conform to the evolving shape of the tumor. “Right now, we take a CT scan before treatment, make a plan, and deliver the plan, but there’s still a lot of finger-crossing going on, given the uncertainties of patient position, patient changes, and organ-shape changes,” he says. “IGRT is going to help us address all those uncertainties.”

Williams agrees, adding, “People have been saying for 25 years that radiation oncology will ultimately fall by the wayside in favor of some other advance in medical oncology. As it turns out, we’re using radiation more rather than less in comparison to a generation ago. I don’t really see any end to that. Radiological therapy has been around for more than 100 years, and we’re just now learning how to give it. The advances on the horizon will tremendously benefit the cancer patient. The future of radiation oncology has really never been brighter.”

Side Effects of Radiation Therapy Side effects from radiation treatment are generally divided into two categories: short-term (acute) and long-term (late). Acute effects constitute the body’s reaction in the immediate weeks and months after treatment. Late effects develop gradually over several months or years. Side effects vary in degree and type, and they depend on the localized area of treatment and the amount of normal tissue included in the radiation field. Treatments in close proximity to sensitive areas, such as the optic nerve, spinal cord, and gonads, present a greater chance of adverse effects. Acute effects are related to rapidly dividing tissues, according to Samuel Hellman, MD, of the University of Chicago. For example, certain localized treatments might cause temporary hair loss, rectal bleeding, skin redness, mouth sores, fatigue, or nausea. Dennis Hallahan, MD, chairman of the department of radiation oncology at Vanderbilt University (Nashville, Tenn), says that the low doses associated with the IMRT beam have resulted in increased skin dosage in patients, and, in turn, more skin reactions. In some cases, IMRT has precipitated a rise in mucositis in areas adjacent to the tumor, he says. Hellman adds, “Acute effects like these heal. It’s the long-term effects that are more serious.” Late effects of radiation treatment might be slight enough not to cause clinical symptoms, or rare enough to present minimal risk to the individual, according to the BC Cancer Center (BCCC) database. A small percentage of patients, however, could experience adverse late effects that are debilitating and difficult to treat. Late effects might include an increase in connective tissue, fibrosis, and scarring that is often associated with atrophy of accessory tissues. Heightened tissue rigidity and less resistance to injury could follow. Gonads subject to high doses of radiation are subject to genetic damage, though the result is usually sterility rather than an abnormal child. And in rare cases, since radiation is a cause of cancer, leukemia could emerge 5?20 years after treatment, due to damage of bone marrow cells during therapy. Other cancers also might manifest in a similar time frame, according to the BCCC database. Tim Williams, MD, of the Lynn Regional Cancer Center notes that certain studies on late effects are not necessarily applicable, considering today’s advanced therapeutic procedures. “Treatment methods in the 1960s and 1970s used entirely different doses and calculation methodologies,” he says. “Back then, we had a lot less knowledge of how much radiation was going where. Although a small percentage of cases are subject to late effects, by and large, radiation therapy is considered a safe treatment.”

?MD

Mark Dye, RT, is a contributing writer for Medical Imaging.