Helical Tomotherapy: An Innovative Technology and Approach to Radiation Therapy

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1 Technology in Cancer Research & Treatment ISSN Volume 1, Number 4, August (2002) Adenine Press (2002) Helical Tomotherapy: An Innovative Technology and Approach to Radiation Therapy Helical tomotherapy represents both a novel radiation treatment device and an innovative means of delivering radiotherapy. The helical tomotherapy unit itself is essentially a hybrid between a linear accelerator and a helical CT scanner for the purpose of delivering intensity-modulated radiation therapy (IMRT). The imaging capacity conferred by the CT component allows targeted regions to be visualized prior to, during, and immediately after each treatment. The megavoltage CT (MVCT) images supplant the port-films used in conventional radiotherapy, providing unprecedented anatomical detail. Image-guidance through MVCT will allow the development and refinement of the concept of adaptive radiotherapy, the reconstruction of the actual daily delivered dose (as opposed to planned dose) accompanied by prescription and delivery adjustments when appropriate. In addition to this unique feature, helical tomotherapy appears capable of further improvements over 3-dimensional conformal radiation therapy and non-helical IMRT in the specific avoidance of critical normal structures, i.e. conformal avoidance, the counterpart of conformal radiation therapy. Based on radiobiological principles that exploit the physical advantages of helical tomotherapy, several dosimetric and clinical investigations are underway. James S. Welsh, M.S., M.D. * Rakesh R. Patel, M.D. Mark A. Ritter, M.D., Ph.D. Paul M. Harari, M.D. T. Rockwell Mackie, Ph.D. Minesh P. Mehta, M.D. Department of Human Oncology University of Wisconsin School of Medicine 600 Highland Avenue Madison, WI 53792, USA Introduction The development of three-dimensional conformal radiation therapy (3D-CRT) was a significant step forward in Radiation Oncology as this technology represented a substantial improvement over conventional therapy in the ability to precisely conform to tumor volumes thereby decreasing radiation dose to nearby normal tissues. Intensity modulated radiotherapy (IMRT) is the most recent technology in the field of radiation therapy and represents yet a further advance in radiotherapy treatment planning. The enhanced dose conformality to tumor volumes allows greater precision in tumor targeting, which in turn permits escalation of dose without concomitant increase in normal tissue toxicity. The clinical application of IMRT is currently in its infancy. Extension and refinement of the concepts of IMRT led to the development of helical tomotherapy. Helical tomotherapy, with its unique design and features, has the potential to provide even further improvements in radiotherapy precision, thereby allowing dose escalation, and possible reductions in overall treatment time. The original concept, first developed by Dr. Thomas Mackie of the University of Wisconsin, was based on a linear accelerator housed within a CT unit capable of both imaging and treating patients (1, 2). As the concept grew into reality, this Abbreviations: IMRT, intensity-modulated radiation therapy; CT, computed tomography; MVCT, megavolt CT; CRT, conformal radiation therapy; CHART, continuous hyperfractionated accelerated radiation therapy. * Corresponding Author: James S. Welsh, M.S., M.D. welsh@mail.humonc.wisc.edu 311

2 312 Welsh et al. device promised to deliver IMRT with several advantages offered by no other systems. For example, the CT component of the helical tomotherapy device allows on-line megavoltage CT (MVCT) imaging, which in turn permits verification of patient positioning prior to and during treatment, reconstruction of delivered radiation dose, and target tumor/organ registration to account for internal motion and tumor shape or volume changes (3). These processes allow for ongoing verification and rapid correction of treatment variations, forming the core of the concept of adaptive radiotherapy. In addition to adaptive radiotherapy, helical tomotherapy may provide a superior means of delivering conformal radiotherapy in many instances. A key concept of the helical tomotherapy strategy is conformal avoidance, the counterpart of conformal therapy. Preliminary dosimetric modeling in many cases suggests comparable or superior radiation dose-distributions than that obtained with non-helical IMRT from a conventional linear accelerator (4-6). These capabilities of helical tomotherapy allow exploration of radiobiologically attractive venues of radiotherapy such as accelerated fractionation with concomitant dose-escalation, which were formerly prohibited by normal tissue toxicity. Physical Design of the Helical Tomotherapy Unit The helical tomotherapy unit merges several features of a conventional linear accelerator with those of a helical CT scanner (Figure 1). Conceptually it can be thought of as a CT scanner that harbors a 6 MV linear accelerator rather than a diagnostic x-ray tube as its source of x-ray photons. A 6 MV fan beam similar to that of conventional diagnostic CT can be used to acquire MVCT images. The helical tomotherapy unit can deliver treatment through this rotating, intensity-modulated fan beam. This contrasts with standard radiotherapy, which is typically given by a few static fields. With the patient continuously translated through a ring-like gantry while the fan beam rotates, the treatment beam forms a helical shape. The intensity modulation is provided by a set of binary collimator leaves that rapidly transition between open (leaf retracted) and closed (leaf blocking) states. When operating as an MVCT imaging system the leaves are retracted to the open state. The beam delivery is similar to that of computed tomography (CT) and requires slip rings to transmit power and data. A ring gantry provides a stable and accurate platform to perform tomographic verification of both the patient setup and delivered dose. Xenon detectors in the ring gantry detect incident x-rays thereby allowing construction of anatomically detailed patient images. Helical tomotherapy has some similarities to the NOMOS Peacock system currently in clinical use. The Peacock system also uses an intensity-modulated fan beam, but because it has an attachment to a standard C-arm linear accelerator, treatment delivery is restricted to a translatethen-rotate method rather than continuous helical delivery; it is not capable of 360-degree rotational treatment delivery. A continuous helical delivery approach may consume less time for each treatment. This may provide radiobiological advantages over other IMRT approaches that can often take several minutes to execute. In addition to the mechanically advantageous method of delivering IMRT, perhaps the greatest step forward presented by helical tomotherapy is the ability to provide accurate verification of the delivery using the principles of tomographic imaging and dose reconstruction. Adaptive radiotherapy Figure 1: The helical tomotherapy unit merges a 6 MV linear accelerator with features of a helical CT scanner, such as a fan-shaped photon beam and xenon detectors for imaging capability, to provide a unique means of delivering intensity modulated radiotherapy. Adaptive radiotherapy encompasses several specific processes, each of which represents a separate capability of helical tomotherapy. The key processes of adaptive radiotherapy include 3-D imaging which is utilized to generate an optimized intensity-modulated treatment plan, setup verification via MVCT, delivery modification to account for setup errors, treatment delivery, dose-reconstruction, and deformable dose registration (7, 8). Adaptive tomotherapy uses information obtained during previous fractions, to correct or modify an ongoing treatment. For instance, dose reconstruction provides feedback to correct errors during delivery. These processes can be viewed as a closed-circuit loop, as illustrated in Figure 2 and Table 1. In order for this approach to adaptive radiotherapy to be suc-

3 Helical Tomotherapy 313 Table I A hypothetical example of adaptive radiotherapy 1. During the few days of treatment, due to some systematic error, the patient was shifted 0.5 cm in the x-direction with respect to the initial plan position. 2. Dose reconstructions of the actual delivered radiation doses are performed and the cumulative tumor dose is computed 3. This data is used as input to re-optimize the plan for subsequent fractions. 4. The delivery during the subsequent few days compensates for the inadequacies of the first few treatments. Having corrected the error detected, the original plan can be properly executed and completed with the patient correctly positioned. Figure 2: Conceptual flow diagram of adaptive radiotherapy illustrating the value of the CT imaging capacity of helical tomotherapy cessful, the MVCT images obtained from the helical tomotherapy unit must be of sufficient quality for tumor identification and targeting. One of our ongoing studies aims to verify this point. Preliminary results indicate MVCT images of lung tumor volumes are subjectively quite comparable to images obtained from the diagnostic CT scanner and do appear adequate for the purposes of radiotherapy treatment planning. The ability to perform repeated MVCT imaging during the course of treatment and to make corresponding corrections in the treatment delivery will allow dose escalation with less risk of normal tissue complications or geometric miss of the target. For example, in our planned lung cancer studies, intra-treatment MVCT imaging will be performed, thus verifying tumor location relative to delivered radiation dose that is more accurate than a pre-treatment CT scan. Aggregate information from these acquired MVCTs can then be utilized to modify subsequent treatments. Conformal Avoidance Conformal external beam radiotherapy techniques, such as 3D-CRT and IMRT, permit improved tumor-targeting accuracy through previously impractical beam angles and advanced beam shaping. These beam-shaping techniques in turn result in more precise conformation of radiation dose to the geometry of the tumor (9). This amounts to an enhancement of the therapeutic ratio (i.e. the ratio of tumor dose to normal tissue dose), which in principle should result in improved treatment outcomes. The counterpart to this concept of conformal therapy is conformal avoidance i.e. the specific avoidance of key normal structures. This strategy may prove easier to routinely execute than conformal targeting. Due to the possibility of internal organ motion, along with tumor size and shape changes during radiotherapy, precision conformality to the targeted tumor carries the potential for geographic miss despite adequate patient immobilization techniques. Conformal avoidance takes these currently uncontrollable events into consideration by providing full dose radiation to the desired cancer-bearing regions while specifically targeting sensitive normal structures for avoidance. These normal tissue structures (i.e, parotid gland, mandible, optic chiasm) are generally much easier to precisely delineate on CT/MR images than are the complex tumor volumes with associated nodal risk regions common for several anatomic sites. In this way the radiation oncologist can be more confident that the patient s tumor has been fully irradiated while simultaneously minimizing risk of radiation-related damage to normal tissues. The physical design and delivery method of helical tomotherapy should permit full clinical exploitation of the concept of conformal avoidance (10, 11). Radiobiologically-Based Clinical Applications Prostate cancer represents the most common non-skin cancer in American males and is a significant source of morbidity and mortality. In order to improve outcomes with radiotherapy, many investigators have escalated the dose to the prostate gland. The high rate of disease recurrence or persistence in intermediate to high risk prostate cancer patients following conventional radiation provides a strong rationale for delivery of higher than standard doses. A dose-response relationship for improved local tumor control with doses of greater than 70 Gy has been well-established (12-14). However, increasing the delivered radiation dose with conventional treatment methods is limited by potential toxicity to the nearby critical structures, specifically the rectum and the bladder (15, 16). The use of 3-D conformal radiation therapy has allowed higher doses to be delivered to the target volume by minimizing dose to normal tissue (17, 18). The advent of IMRT has allowed additional tailoring of the treatment portals resulting in further reduction in acute toxicity relative to 3Dconformal techniques (19, 20). Conformal delivery with its smaller treatment margins requires greater accuracy and

4 314 Welsh et al. reproducibility in target localization and patient set-up. This is crucial in avoiding geographic misses which underdose the target volume or overdose the surrounding normal structures. Current conformal technology is limited by cumbersome and uncertain methods for verifying target and normal organ positions as well as delivered dose (21, 22). Conventional radiotherapy fractionation schemes employing fraction sizes of Gy are based upon the radiobiological premise that tumors typically respond differently to fractionation than do late-responding normal tissues. The α/β ratio, a parameter derived from cell-survival curves in response to irradiation, correlates with fractionation response. Generally, low α/β ratios (e.g. 3) are associated with late responding normal tissues. This suggests greater DNA damage repair between fractions with relative damage sparing when small fraction sizes are administered. Most tumors, on the other hand, have higher α/β ratios (e.g. 10) and thus are quite effectively treated using multiple small fractions (23). Growth fraction (or average cell cycle time) often correlates with fractionation response, with slowly proliferating normal tissues (and some slowly proliferating tumors) generally displaying fractionation responses characteristic of a low α/β ratio. In the case of prostate cancer, there is ample evidence for slow proliferation, based upon both direct in-vitro measurement of potential doubling times and labeling indices as well as analysis of the kinetics of rising PSA during tumor recurrence (24, 25). Analysis of clinical isoeffect curves (e.g. similar tumor control) generated using varying fractionation schemes also provides a means of estimating α/β ratios. Recent analyses have argued for a very low α/β ratio (~1.5 Gy) for prostate cancer (26-28). These analyses and supporting clinical data imply that hypofractionation (i.e. increased daily fractional dose) should be systematically investigated in prostate cancer. Potential advantages of such dose-per-fraction escalation include relatively less acute toxicity, fewer overall fractions, and a shorter treatment course. In order to safely execute such a hypofractionation strategy, however, it is crucial to have precise and accurate tumor targeting. Helical tomotherapy offers advantages over other external beam radiation approaches in terms of the degree of conformality achievable and the ability to directly confirm organ position and delivered dose. This new conformal treatment planning and delivery system will be used in a Phase I study to explore the clinical feasibility of delivering hypofractionated radiotherapy for prostate cancer while maintaining acceptable levels of normal tissue toxicity. In addition to potential improvement in tumor control, this hypofractionated approach could result in substantial improvement in patient convenience and in cost effectiveness through a reduction in the total number of treatments needed to complete a course of therapy. Accelerated Fractionation In addition to the rationale for hypofractionation in prostate cancer, there are reasons to investigate alternative fractionation schemes in other cancers. For instance, dose escalation by simply increasing the number of conventionally-sized fractions results in prolongation of overall treatment time. Two opposing forces are at work in such prolonged schedules: increased clonogenic death and accelerated repopulation. Increased tumor cell kill, an obviously favorable result, is due to the increased total radiation dose during the course of therapy. Accelerated repopulation, which antagonizes the effect of dose escalation, is due to clonogens decreasing their cell-cycle time and increasing their overall proliferation rate after prolonged exposure to radiation. This effect may not be adequately overcome by the increased dose in protracted schedules. An example which supports schedule-shortening in the management of non-small cell lung cancer utilized an accelerated hyperfractionation scheme known as continuous hyperfractionated accelerated radiation therapy or CHART employing three fractions per day over a 2-week course of treatment. The results of this randomized trial of 563 patients demonstrate a 9% survival benefit (p= 0.008) at 2 years for patients randomized to CHART compared to standard oncedaily radiation to 60 Gy over 6 weeks (29). Until recently the proliferation rate of NSCLC was not well known. Analysis of Radiation Therapy and Oncology Group (RTOG) data suggests the importance of overall treatment time in both local control and survival in non-small cell lung cancer. Of 397 lung cancer patients treated on this RTOG study, 70 had treatment delays of 5 or more days. These patients were observed to have 1- and 3-year survival probabilities of 37% and 1% respectively, versus 56% and 17% in patients without treatment delays. The median loss in survival probability was calculated to be 1.6% per day of prolongation beyond 6 weeks. This rate of loss of tumor control with treatment prolongation computes to a clonogen doubling time of 3 to 3.5 days for both head and neck and non-small cell lung cancer (30). Jones and Dale (31) have suggested that for tumors with very short potential doubling times, an increase in dose per fraction may be a more effective means of delivering the extra dose required to overcome accelerated proliferation than an increase in the number of fractions. For this reason our dose escalation efforts with helical tomotherapy are largely focused on shortening the overall treatment schedule and increasing daily fraction size (i.e. accelerated hypofractionation). A secondary advantage of such a strategy is the reduction in psychological and economic hardship imposed on patients by a prolonged course of therapy. In the United States, one of the major drivers for radiotherapy cost is the duration of treatment. Prolongation of radiotherapy from 6 weeks to 10 weeks is likely to result in a

5 Helical Tomotherapy % increase in the overall cost of that radiotherapy. With helical tomotherapy, it should be feasible to achieve doseescalation, using the dose-per-fraction escalation method, and avoid increases in resource consumption and expenses. A dose-per-fraction escalation strategy is only possible in the context of highly conformal dose-distributions to minimize late normal tissue toxicities. This theme is the focus of our ongoing lung cancer helical tomotherapy research projects. Given the potential doubling time of around 3 days, prolongation of treatment may not be the ideal method of dose escalation. With tomotherapy it should be possible to treat limited volumes of normal tissue through conformal avoidance and escalate dose per fraction, maintaining a constant low risk of late complications. The decreased duration of the full treatment course should increase tumor control probability by increasing the biologically effective dose and avoiding accelerated proliferation. Our strategy is to first test conventional fractionation schedules with tomotherapy, confirm safety in a preliminary group of patients, then decrease the overall duration by increasing fraction size. In the case of lung cancer, modeling data suggests that the optimal reduction in duration is to approximately five weeks (30, 32). Thereafter, we plan to perform a phase I study escalating the total dose without increasing duration, i.e. by escalating fraction size. For this dose escalation strategy to be successful, helical tomotherapy will be utilized to produce conformal dose distribution around a well-defined tumor and to minimize the volume of normal lung irradiated, exploiting conformal avoidance capabilities. The MVCT imaging capabilities of helical tomotherapy and the adaptive radiotherapy strategy will be critically important in restricting the volume of lung irradiated so as to implement this dose-escalation strategy safely. Conclusion With its novel physical design and method of delivering IMRT, helical tomotherapy holds great promise for the future enhancement of Radiation Oncology. Along with adaptive radiotherapy (shared by no other current approach), development and refinement of the concepts of conformal avoidance and radiobiological dose optimization offer promising opportunities for cancer specialists and for the cancer patients who stand to benefit from this new technology. References and Footnotes Mackie, T. R., Holmes, T., Swerdloff, S., et al. Tomotherapy: A new concept for the delivery of dynamic conformal radiotherapy. Med Phys 20, (1993). Mackie, T. R., Balog, J., Ruchala, K., et al. Tomotherapy. Semin Radiat Oncol 9, (1999). Ruchala, K. J., Olivera, G. H., Kapatoes, J. 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