Advances in Image-Guided Radiation Therapy
Imaging is central to radiation oncology practice, with advances in radiation oncology occurring in parallel to advances in imaging. Targets to be irradiated and normal tissues to be spared are delineated on computed tomography (CT) scans in the planning process. Computer-assisted design of the radiation dose distribution ensures that the objectives for target coverage and avoidance of healthy tissue are achieved. The radiation treatment units are now recognized as state-of-the-art robotics capable of three-dimensional soft tissue imaging immediately before, during, or after radiation delivery, improving the localization of the target at the time of radiation delivery, to ensure that radiation therapy is delivered as planned. Frequent imaging in the treatment room during a course of radiation therapy, with decisions made on the basis of imaging, is referred to as image-guided radiation therapy (IGRT). IGRT allows changes in tumor position, size, and shape to be measured during the course of therapy, with adjustments made to maximize the geometric accuracy and precision of radiation delivery, reducing the volume of healthy tissue irradiated and permitting dose escalation to the tumor. These geometric advantages increase the chance of tumor control, reduce the risk of toxicity after radiotherapy, and facilitate the development of shorter radiotherapy schedules. By reducing the variability in delivered doses across a population of patients, IGRT should also improve interpretation of future clinical trials.
Advances in three-dimensional radiation therapy planning have led to the safe delivery of escalated doses to tumors, improving local control and sparing dose to healthy tissues improving quality of life (eg, head and neck cancer treated with salivary gland sparing).An inherent goal of all radiotherapy treatment is that radiation be delivered to the target volumes as planned. Imaging at the time of radiation treatments increases the confidence with which this occurs. Despite interventions to immobilize patients at the time of radiation therapy, residual uncertainties in the position of tumor and healthy tissues persist. Without image guidance at the time of therapy, changes in position, shape, and breathing motion may prevent the desired dose from being delivered to the patient.The rapid fall-off in dose outside the target associated with highly conformal radiotherapy techniques drives demand for accurate target delineation at planning and target localization before treatment delivery to avoid underdosing the target. The requirement for target localization increases further as the number of fractions is reduced and the potency of dose delivered is increased (eg, stereotactic body radiotherapy [SBRT]).
Radiotherapy planning, delivery, and verification involve a large spectrum of imaging and imaging-based decision making. For the purposes of this review, image-guided radiotherapy (IGRT) focuses on the imaging and guidance activities in the radiation treatment room during a course of external-beam radiation therapy.
TARGET LOCALIZATION: FROM SKIN MARKS TO IMPLANTED MARKERS
In conventional approaches, the radiation therapy patient is positioned before treatment by inferring the location of internal anatomy from surface marks. However, the internal anatomy is not always well correlated with the surface anatomy. Images produced using the megavoltage (MV) treatment x-ray beam itself were some of the first methods of imaging internal anatomy at the time of treatment (using film or digital imaging approaches generated with flat-panel detectors). Radiographs obtained using MV x-rays have lower contrast than those from conventional radiographic imaging (kilovoltage [kV] x-rays). Using the treatment beam, the position of the skeleton relative to the treatment field edge can be compared with reference images produced during the radiation planning process, and adjustments to the patient position can be made. Unfortunately, many tumors are not in direct continuity with bones, and some soft tissues can move considerably relative to the bones. One method of targeting tumors with radiographic approaches is to implant radiographic markers in or near the tumor. This has been used to improve localization of prostate lung,pancreatic, paraspinal, and liver cancers.Occasionally, the tumor or structures close to the tumor (surrogates) may be seen on MV images to aid target localization. For example, the diaphragm has been used as a surrogate for guiding the treatment of liver tumors. Because of the contrast limitations associated with MV x-rays, machine- and room-mounted kV x-ray tubes and efficient x-ray detectors have been applied to radiotherapy treatment rooms to improve imaging at the time of radiation delivery. The kV x-rays provide higher contrast for bony structures or metal markers, detected at far lower imaging doses. kV fluoroscopy has been used to frequently image radio-opaque markers (smaller than those required for MV imaging) before each radiation fraction or throughout radiation delivery. A variety of kV-based IGRT systems have been reported in the literature. Benefits of kV fluoroscopy are illustrated in a pioneering "real-time tumor tracking" approach developed by Shirato in which tumors that move due to breathing are exposed to radiation only when the markers are located within a predefined volume. Alternative approaches involve tracking the tumor with moving collimators to "chase" the tumor or dynamically controlling the couch or the accelerator movement to follow the markers (eg, Cyberknife; Accuray Inc, Sunnyvale, CA).More recently, advances in microelectronics have allowed the creation of radiofrequency transponders (or miniature global positioning systems) that can be inserted in or near the tumor. These systems are coupled with a local antenna array that can sense and locate the transponders relative to the treatment beam (Calypso Medical Technologies, Seattle, WA).
TARGET LOCALIZATION: IMAGING OF TARGET AND NORMAL STRUCTURESVolumetric imaging has been developed to allow the tumor and surrounding organs to be visualized at the time of radiation delivery. Ultrasound and in-room computed-tomography (CT) scanners were the first methods of routine volumetric imaging at treatment delivery. Transabdominal ultrasound has been used for pelvic and upper abdominal tumor IGRT. In-room CT (eg, Primatom; Siemens Medical Systems, Concord, CA; ExaCT; Varian Medical Systems, Palo Alto, CA) allows a diagnostic-quality CT scan to be obtained immediately before therapy, with a displacement in couch position required between the time of imaging and treatment. In-room CT has been used to monitor volumetric change occurring during head and neck cancer radiotherapy, and for guidance in upper abdominal malignancies and paraspinal tumors.
Helical MV CT scans can be obtained using a novel treatment unit (TomoTherapy, Madison, WI) which allows the MV treatment beam to rotate around the patient while the couch moves through the bore. Single-slice or volumetric MV images of the irradiated region can be constructed. This system is in routine use for IGRT and offers images of a quality that can be readily utilized for dose recalculation.
Cone-beam CT refers to tomographic reconstruction from a series of two-dimensional radiographs obtained in a single rotation of source and detector around the patient. Cone-beam CT systems integrate a kV tube and a flat-panel detector mounted on a linear accelerator (eg, Synergy, Elekta Oncology, Stockholm, Sweden; On Board Imager [OBI], Varian Medical Systems; Artiste, Siemens). The same axis of rotation is shared between the kV imaging and MV treatment beams, and the central axis of the kV beam is oriented perpendicular to (Synergy and OBI) or parallel to (Artiste) the treatment MV beam. Hundreds of projections are acquired over a 30- to 240-second interval while the volumetric reconstruction proceeds in parallel. kV cone-beam CT images have been acquired in most body parts for image guidance and verification. Respiratory-sorted kV cone-beam CT scans (referring to volumetric imaging acquired at different phases of the respiratory cycle or so-called four-dimensional cone-beam CT) allow the changes in tumor and normal position due to breathing to be measured. These systems can also produce kV fluoroscopic images from any gantry position, and they have the potential for real time (ie, concurrent with the MV radiotherapy treatment) fluoroscopic tumor monitoring and tracking (not yet available for routine clinical use).Cone-beam CT using the MV beam (MV cone-beam CT) has required less modification to a conventional linear accelerator compared with MV tomotherapy or kV cone-beam CT.The MV beam itself is used to construct a cone-beam CT, in a similar manner to the way kV cone-beam CT scans are obtained, with a single rotation around the patient. MV cone-beam CT image guidance has been particularly useful for IGRT of paraspinal tumors in patients with orthopedic hardware in place, which can cause artifacts on kV CT scans.
The advent of IGRT is spurring the development of another generation of treatment machines. Kamino have recently reported a new ring-gantry system that offers cone-beam CT imaging along with a tilting treatment head for tumor tracking using kV fluoroscopy. The interest in tracking is also reflected in the two new initiatives to build MR-guided RT systems.
In addition to generating images with sufficient contrast for detection, the systems must deliver high geometric precision and accuracy for guiding the positioning of the patient. Because the goal of these imaging systems is to localize tumor, without the need to diagnose new tumors, imaging doses can be reduced substantially compared with those for diagnostic CT scans (eg, 20- to 100-fold lower than the dose for a diagnostic CT scan). All of the clinic systems reported here are capable of submillimeter precision and accuracy for higher contrast objects. The experience of the authors has demonstrated that the additional quality assurance associated with these activities is not overwhelming and can be integrated into existing quality-assurance activities.
STRATEGIES TO IMPROVE RADIOTHERAPY TARGETING
The technological innovations described herein can be deployed in a variety of ways depending on tolerance for geometric imprecision, resource constraints, imaging dose, and number of radiation fractions in a treatment course. In general, image-guided adjustments can be grouped into two categories: on line and off line. When the images are evaluated before each radiation treatment, with corrections or actions occurring at the time of radiation delivery on the basis of predefined thresholds, this is referred to as on-line correction. An on-line correction proceeds as follows: imaging before each treatment, alignment of the reference and current image and repositioning of the patient. Alternatively, an off-line approach refers to the acquisition of frequent images during a course of radiation therapy without immediate intervention. After a small number of radiation fractions have been delivered, the systematic (and most important component of geometric uncertainties) can be calculated, and a correction applied by repositioning the treatment couch for all future fractions.When weight loss or shrinkage or deformation of tumor and healthy tissues are seen during therapy, developing a second radiation plan on the basis of the new anatomic information may be the best way to adapt to the change. This practice is referred to more generally as adaptive radiation therapy. Substantial technological advancements are necessary in the automation of planning and error correction before replanning can be conducted frequently in the clinic setting. The clinically meaningful thresholds for replanning are not yet known. Another area of research is in predicting geometric change and developing radiation plans that are robust to geometric change (ie, plans that will deliver the intended dose despite uncertainties).
BENEFITS OF THE IGRT PROCESS
IGRT has increased our awareness of set-up error and motion during radiation delivery and between fractions. Day-to-day variability in tumor position relative to the skeleton has been shown to be substantial. Interpatient, intrapatient, and intrafraction variations in the motion of lung and liver cancers because of breathing have also been observed in patients treated with real-time fluoroscopic tracking, and the complexities of breathing motion have become more apparent. Changes in the baseline tumor position relative to the skeleton have been observed in lung and liver cancer patients treated with repeat breath holds to immobilize the tumor, providing rationale for daily IGRT for cancers treated with breath hold. Millender observed very large positioning errors of the prostate in obese men (systematic and random errors in the right-left direction of 11.4 and 42 mm, respectively), forming the basis for IGRT for this population to reduce set-up error.
It has been demonstrated in most body sites that IGRT reduces the set-up error and the volume of healthy tissue adjacent to the target that is required to be irradiated. Orthogonal MV imaging and kV imaging, using implanted radio-opaque markers or soft tissue surrogates for tumor, can reduce set-up error. Real-time tumor tracking significantly reduces the volume of lung and liver irradiated because of breathing motion.Ultrasound guidance of vascular structures as surrogates for upper abdominal tumors and for prostate cancer significantly improves the residual set-up error. Finally, volumetric image guidance (eg, with kV or MV cone-beam CT or MV tomotherapy) can reduce the volume of irradiated healthy tissue in prostate, lung, liver,bladder, and head and neck cancers.
In addition to set-up error and organ motion, change in the shape and volume of the tumor and healthy tissues can now be measured using volumetric imaging acquired at the treatment unit. In some situations, these changes are larger than expected, and the use of image guidance reduces the possible negative impact on the delivered doses. Weight loss in head and neck cancer patients has led to an increase in spinal cord dose that would not have been detected in the absence of frequent imaging during radiotherapy. Another study demonstrated that IGRT and adaptive replanning of lung cancer resulted in an average reduction of 21% in the volume of lung receiving 20 Gy or more, with a resultant reduction in the risk of toxicity.
As geometric precision improves with IGRT, the clinical benefits of the reduction in healthy tissue irradiated with the use of IGRT should follow.Because linear accelerators capable of volumetric IGRT are relatively new, multicenter clinical trials requiring IGRT have not yet been reported on. The clinical benefits of conformal radiotherapy and SBRT and other technological advances in radiation oncology are only beginning to be realized. Because image-guidance technologies provide confidence in the dose placement, the actual delivered doses can be verified and documented, giving rise to less variability in dose across a population. This should allow the benefit of other advances in radiation therapy (conformal radiotherapy, intensity-modulated radiotherapy [IMRT], dose escalation, hypofractionation) to be more clearly evaluated. Clinical trials incorporating IGRT are ongoing. The increased precision and accuracy from IGRT should lead to increased local control rates in these trials, with a reduction in toxicity in healthy tissue (compared to the same regimen without IGRT). The evaluation of IGRT using the conventional randomized trials approach will be challenging because of the indisputable nature of the underlying rationale (ie, to deliver the dose to the target and avoid normal structures). However, the radiation oncology community needs to take up the challenge of demonstrating the benefit of these potentially expensive approaches.
The clinical situations most likely to benefit from IGRT include those in which the tumor is in close proximity to sensitive healthy tissues, the doses required to control the tumor are higher than the tolerance levels of adjacent normal tissues, the consequence of a positioning error are severe, and organ motion and set-up error are large. For example, patients treated with conformal radiotherapy, IMRT, and SBRT should benefit from IGRT. Tumors of the thorax and upper abdomen and cancers in obese patients that move substantially should also benefit from IGRT. Other clinical sites that should benefit from IGRT include head and neck cancer, paraspinal and retroperitoneal sarcomas, and prostate cancer. Situations expected to benefit less from IGRT are sites where local control is excellent despite low-dose irradiation, large-field low-dose palliative radiotherapy, and skin cancer (that which can be localized by direct visual inspection).
As an example of how radiotherapy technique may influence clinical outcomes, the rectum size at the time of radiotherapy planning in prostate cancer patients treated without image guidance has been associated with clinical outcomes.The 6-year prostate-specific antigen–free survival of patients with full and empty rectums were 65% and 80% respectively (hazard ratio, 3.89; 95% CI, 1.58 to 9.59; P = .003). This change in outcome may be related to the fact that a distended rectum at planning (caused by gas or fecal material) is less likely to be distended during treatment, leading to the prostate's moving posteriorly, out of the high-dose volume. IGRT could reduce this adverse effect.
Investigations of the spatial recurrence patterns after radiotherapy and the relationship of recurrences to the dose delivered should provide insight to benefits from IGRT. Trials comparing high-precision radiotherapy with IGRT compared with low-dose palliative radiotherapy should also be considered in clinical situations in which the role of radiotherapy is not yet established (eg, for isolated or oligo metastases) to attempt to measure the benefits of technological advances in radiation oncology.
Potential weaknesses of IGRT are that no one technology or strategy is ideal for every scenario. The technologies need to become more integrated with preexisting infrastructure. Although the doses from IGRT (very low compared with MV portal imaging) appear insignificant, over a long course of therapy—especially if combined with IMRT—long-term follow-up is required before risk of second malignancy can be known with confidence. In the meantime, research to determine the minimum required IGRT strategy for each clinical situation, with the lowest imaging dose and imaging frequency, is ongoing. Finally, as we deliver radiotherapy more precisely, there are diminishing returns for more sophisticated advances. In this context, other uncertainties such as tumor detection and delineation errors become more important.