Figure 8: An example of conformal helical tomotherapy for NSCLC demonstrating the ability to effectively target areas of disease while simultaneously minimizing dose to normal lung. Such dose distributions may allow clinical implementation of dose-fractionation schemes previously considered impractical or risky.

In a separate study, five patients with inoperable stage III NSCLC were formally studied, representing a variety of tumor sizes and locations (42). For each patient, two treatment plans were generated: one using optimized 3D treatment planning techniques and one using helical tomotherapy. Normal tissue V20, NTDmean, and effective uniform dose (EUD) for a given tumor dose were compared and tumor doses possible for a given mean normalized lung dose were also computed and compared. In order to obtain a meaningful comparison, the helical tomotherapy plan was optimized with the objective of minimizing normal tissue doses as much as possible while using an equivalent planning target volume dose as the 3D plan. The lung doses were significantly lower with helical tomotherapy in all five cases. For the lungs taken together as a single organ, the mean normalized doses with tomotherapy planning ranged from 2.05 Gy to 8.36 Gy (mean 5.7 Gy), versus 4.4 Gy to 13.62 Gy (mean 8.1 Gy) with 3D planning. The V20 for both lungs was also lower in each case with helical tomotherapy. On average, for both lungs, helical tomotherapy allowed a 22% reduction in V20 and a 30% reduction in NTD mean when compared to 3D planning. The mean spinal cord dose was also markedly lower with helical tomotherapy. Based on these data we conducted a virtual dose-escalation trial and concluded that helical tomotherapy has the potential to significantly decrease radiation dose to lung and other normal structures in the treatment of NSCLC. This has important implications for dose escalation strategies in the future.

Increasing BED by Dose-per-Fraction Escalation:
Prostate Cancer

The BED-dose escalation strategy will also be tested for prostate cancer. Retrospective studies have indicated a substantial dose response for prostate cancer. Hanks et al. examined Patterns of Care data and found actuarial local recurrence rates of 37% for T3 patients treated to less than 60 Gy, 36% for doses of between 60-64.9 Gy, 28% for 65-69.9 Gy, and 19% for doses of 70 Gy or more (43). Similarly, Perez et al. found 38% local recurrences for doses less than 60 Gy, 20% for doses between 60, and 70 Gy and only 12% for doses of 70 Gy or greater (44). A randomized trial has confirmed superior PSA recurrence-free survival when greater than 70 Gy was delivered, for intermediate or higher risk patients (45). These results provide a strong rationale for the delivery of higher than conventional radiation doses. When delivered with conventional techniques, however, doses higher than 70 Gy are associated with higher complication risks (46). It has now become clear that 3D conformal radiotherapy demonstrates better than historically expected tolerance of normal tissues to higher doses, but complication rates, particular rectal bleeding, can still be substantial (47). Various analyses suggest that the total area of rectal wall exposed to greater than 60 or 70 Gy predicts the rate of rectal bleeding. Therefore, the implementation of IMRT, with its ability to reduce rectal irradiation, can reduce toxicities (48). Such IMRT strategies are compromised by prolonged schedules and higher costs. Therefore, analogous to our NSCLC approach but for different radiobiological rationale, we plan to evaluate dose-per-fraction escalation, maintaining a constant schedule length and utilizing fewer fractions.

The radiobiological basis for utilizing this option in prostate cancer is its uniquely slow proliferation rate compared with other tumor types. The labeling indices (LI) for prostate cancer are extraordinarily low, with most reports suggesting levels below 1%, and a median Tpot value of 40 days (range 15 to 170) (49). Recent suggestions have also been made that the α/β ratio of prostate cancer may be remarkably small (even smaller than 3 Gy, the α/β ratio for many late responding tissues), far below the classic α/β ratios of around 10 for rapidly proliferating neoplasms. Brenner and Hall (50) investigated whether current fractionation schema for the treatment of prostate cancer with radiation could be improved; they analyzed two data sets, one using external radiation and the other permanent seed implants, using the linear-quadratic model for analysis. Their results suggest that prostate cancer may be significantly sensitive to changes in fraction size. They estimated an α/β value of 1.5 (95% CI = 0.8, 2.2), and concluded that external beam radiotherapy for prostate cancer should be designed using larger doses per fraction. We (51) have evaluated additional patient datasets from 1400 patients from 13 centers and confirmed the conclusion that α/β is as low as 1.5 with a narrower 95% confidence range of 1.2-1.8 Gy. Brenner et al. (52) have derived a value of α/β = 1.2 Gy from clinical hypofractionated boost data, although with only 121 patients and a rather short follow-up. Duchesne and Peters (53) have also argued in favor of hypofractionated boosting. Assuming these low α/β estimates, hypofractionation schemes could be designed that would be expected to maintain current levels of tumor control while reducing late sequelae or alternatively, increasing tumor control while maintaining a constant level of late complications. Either approach would provide the logistic and financial advantages of fewer numbers of fractions. We, therefore, propose in Figure 9 that dose escalation studies in prostate cancer should not be achieved by simply increasing numbers of 2 Gy fractions (red line in Figure 9) but instead utilize hypofractionated schedules as indicated in the curves (blue line) rising to the left. This would reduce the numbers of fractions required from around 40 to roughly half that many using daily fractions of 2.5-3 Gy. With further experience, even fewer and larger fractions could be used, with appropriate reduction in total dose, to obtain greater tumor control at the same risk of late complications. This regimen can best be achieved in the context of minimizing the volume of rectal mucosa, and bladder volume exposed to these large fraction sizes. The key focus of research in this study will be safe dose-escalation, using both the rectal balloon technique (54) and conformal avoidance to minimize the volume of rectal mucosa irradiated. While strategies involving biological dose escalation via an increase in dose per fraction are certainly not limited to helical tomotherapy, in our investigations, the exquisite conformal avoidance capabilities of helical tomotherapy will undoubtedly be helpful in permitting the delivery of the large fractions to well-defined prostate volumes and simultaneously avoiding high doses to the rectal mucosa.


Figure 9: Using ten fractions of 4.7 Gy should yield the same late complication probability but increased bNED (biochemical no evidence of disease) as if 72 Gy were increased to 83 Gy in 2 Gy fractions, assuming an α/β ratio of 1.5.

Finally, with helical tomotherapy the larger fractions should not take longer than conventional radiation therapy and may actually be considerably quicker than other forms of IMRT such as ?step and shoot? segmental IMRT and serial tomotherapy. As mentioned earlier this may be advantageous, especially for prostate cancer with its low α/β ratio (4, 5).

IMRT: The Problem Of Motion

Many IMRT approaches rely on increasing the number of beam directions and in modulating beam intensity such that there is consequential creation of multiple tiny sub-beams. While this improves dose-distributions, the clinical applicability of such tiny sub-beams requires immense precision; the slightest patient/organ/tumor motion is likely to result in unintended dose deposition. Therefore, although fantastic dose-distributions and DVHs can be created, their clinical application must be approached with caution. Many patient immobilization systems have evolved to address this issue.

Optical Guidance

Non-invasive head frame systems often rely on external contours of the head and face, and have immobilization errors of 2-4 mm in favorable circumstances. Such systems include the Heidelberg system, which has a reported accuracy of 2 mm (55), the Laitinen's stereoadapter with a measured error of approximately 2 to 3 mm (56), and the Gill-Thomas-Cosman, which uses a maxillary bite block system to yield reproducible immobilization and repeat fixation (57) and a reported accuracy of 0.5 to 1 mm. The optically guided FSRT/IMRT approach in use at the University of Wisconsin is a non-invasive system (Figure 10) where localization is separated from immobilization. This is accomplished through detection of four markers attached to a custom rigid bite plate. The location of these markers in space (tracked relative to the isocenter) is accomplished in real time using an optical position sensor system mounted to the ceiling of the accelerator vault and interfaced with a computer. The interfraction translational error and rotational error is within 0.3 mm and 0.3 degrees, respectively. Tomé et al. (58) have shown that this optically guided system, in conjunction with IMRT planning, allows the generation of highly conformal treatment plans that exhibit smaller 90%, 70%, and 50% prescription isodose volumes, improved PITV ratios (the ratio of the prescription isodose volume to tumor volume), comparable or improved effective uniform dose (EUD), smaller NTD_mean for critical structures, and an inhomogeneity index that is within generally accepted limits. In addition, optically guided treatments allow real-time monitoring of treatment delivery, providing further confidence in the patient?s actual delivered dose distribution. For helical tomotherapy, such optical guidance will be useful in verifying that the patient has not moved between MVCT and treatment.


Figure 10: In this optically guided FSRT/IMRT system, localization is separated from immobilization through detection of four passive markers that are attached to a custom bite plate to form a rigid system. Translations and rotations are tracked in real time using an optical position sensor system mounted to the ceiling and interfaced with the computer. Definition of treatment room stereotactic space relative to the linac isocenter is accomplished using a rigid body calibration apparatus equipped with passive markers that have known locations. The calibration apparatus is precisely positioned relative to the isocenter using a stereotactic floor stand. After calibration, the position of any passive marker in the room may be defined relative to a calibration matrix. Since three points define a plane, any three passive markers in a fixed relationship may be used to define the rotational and translational characteristics of the rigid body relative to this defined virtual space. This system allows one to localize patients between fractions in the treatment room within 0.3 mm-translation error and 0.3 degrees of rotation error.

To demonstrate the clinical relevance, an early implementation of this system is illustrated in Figures 11 and 12. This patient with an astrocytoma required radiotherapy and was planned with 3-D conformal techniques, multi-non-coplanar field FSRT, and IMRT. In all three treatment planning scenarios, CT-MR fusion was utilized and the defined GTV/CTV was constant. A mathematical descriptor, PITV (the ratio of the prescription isodose volume to tumor volume) is frequently employed to evaluate dose-conformality. The ideal PITV ratio is 1; values up to 2 are commensurate with good stereotactic radiosurgery plans. In the example presented in Figure 11, the PITV values are 3.16, 1.65, and 1.45, for the 3-field conventional, 3-D FSRT and helical tomotherapy plans, respectively. The DVHs in Figure 12 reveal substantial improvement in brain stem dose reduction as the technical approach becomes more sophisticated. The superior patient immobilization, day-to-day alignment and position-verification afforded by the FSRT and the IMRT systems using an optically guided system, allowed for a substantial reduction in the PTV margins (59). This margin reduction alone can have a significant impact in improving the DVH. The conformality afforded by FSRT and IMRT lead to dosimetric improvement that might be further improved using helical tomotherapy techniques. The application of immobilization devices is practical, and the incorporation of optical-guidance provides a high degree of reliability in terms of daily positional reproducibility and for monitoring intra-treatment motion, potentially maximizing the inherent benefits of helical tomotherapy.

Figure 11: This pilocytic astrocytoma was treated to a total dose of 45 Gy and treatment planning was performed using three approaches: a standard 3-field, an FSRT, and an helical tomotherapy IMRT approach; the resulting dose-distributions are presented as dose-volume histograms in Figure 12. The tomotherapy plan results in the greatest sparing of normal brain tissue as demonstrated by the PITV values are 3.16, 1.65, and 1.45, for the 3-field conventional, 3-D FSRT, and helical tomotherapy plans, respectively.

Figure 12: DVH comparisons of the various techniques illustrated in Figure 11. The tumor DVHs are illustrated by the three curves in the upper right corner, which demonstrates that the entire tumor receives at least 45 Gy with small proportions up to 49 Gy. Tumor coverage is virtually identical with all techniques. The dose to the brainstem, however, is considerably different. The dose received by 50% of the brainstem is 34 Gy, 17 and 12 Gy with the 3-field, FSRT, and helical tomotherapy methods respectively.

Ultrasound Guidance

The system described above works well as long as the rigid body approximation holds, as is the case for intracranial lesions. However, outside the cranium, soft-tissue targets can move relative to rigid fixation points (e.g., bony structures) between the times of image acquisition, treatment planning, and treatment delivery. Real time imaging is useful in determining target location at the time of treatment delivery. A system based on 3D-ultrasound guidance (SonArray™, ZMed, Inc., Ashland, MA) can be used to correct for these misalignments at the time of treatment. Ultrasound is chosen because it is a flexible and inexpensive imaging modality that can easily be adapted for use in a radiation therapy treatment room. The interpretation of two-dimensional ultrasound images can be challenging and is highly dependent on the skill of the operator in manipulating the transducer and mentally transforming the 2D images into a 3D structure. Three-dimensional ultrasound imaging overcomes this limitation. The 3D ultrasound data sets are generated through optical tracking of free-hand acquired 2D ultrasound images. The position and angulation of the ultrasound probe are determined using an array of four infrared light-emitting diodes (IRLEDs) attached to the probe. An infrared camera is used to determine the positions of the IRLEDs, and this information is input to the computer workstation. The position of each image plane can therefore be determined using the IRLEDs, and an ultrasound volume can be reconstructed by coupling the position information with the images.

In addition to building the 3D image volume, optical guidance is used to determine the absolute position of the ultrasound image volume in the treatment room coordinate system. Because the relative positions of the 3D-image volume and the ultrasound are fixed, knowledge of the probe position in the treatment room coordinate system at the time of image acquisition is sufficient to determine the position of the image volume relative to the linac isocenter. The image to probe relationship is determined by a calibration step performed at the time of system installation (60). In this way, ultrasound guidance will allow greater accuracy of treatment delivery via helical tomotherapy to various extracranial sites.

Currently, ultrasound is being used in conjunction with MVCT. We are presently conducting a comparison of ultrasound versus MVCT. Ultimately, it may be that MVCT alone will be the only image-guidance necessary.

Respiratory Gating

Two strategies have emerged to deal with the problem of respiratory motion. One strategy is to ?immobilize? the lung during one phase of respiration and to gate radiation to this phase. This requires the ability of patients to breath-hold for a short period of time, which may be difficult in patients with respiratory cancers. The second strategy is to radiate at a predetermined period during respiration using dynamic aperture tracking. On-line verification of the correct phase of respiration requires a respiratory monitoring device (61). Another option provided by the helical tomotherapy unit is to determine the phase of respiration using the MVCT. Individual patient respiratory patterns will be assessed during planning and an MVCT can be performed at each treatment. The treatment will then be gated to the predicted respiratory phase with the appropriate dosimetric plan.

Consequences Of ?Hot? And ?Cold? Spots

In order to irradiate in a highly conformal manner, linac-based IMRT often [but not always (70)] results in significant dose variation within target volumes. While helical tomotherapy appears to be highly capable of providing homogeneous dose distributions within targeted regions, in some situations dose heterogeneity might be advantageous. Tomé and Fowler (62) have investigated the effect of selectively boosting tumor regions above the base dose received by the entire tumor. They found that calculated values of TCP increased rapidly with both boost dose ratio and with proportion of volume boosted. The increase in TCP plateaued after boost dose ratios of 1.2-1.3 except where very large proportions of tumor volume exceeding 90% were boosted. Furthermore, quite large increases of TCP, to about 75%, could be achieved if the γ₅₀ slope was steep, and especially in small tumors (having fewer cells). They concluded that there were few situations where a boost dose ratio exceeding 1.3 appeared to be worthwhile or necessary and that significant increase of TCP, up from 50% to 75%, might, therefore, be achieved for a small increase in risk of necrosis, where a substantial proportion of tumor volume (60-80%) could be boosted.

The discussion above assumes that the entire tumor is irradiated to some minimal base dose. In order to study and quantify the effect of a small volume of cold dose on TCP and effective uniform dose (EUD), Tomé and Fowler (63) constructed a four-bin DVH model in which the lowest dose bin, which has a fractional volume of 1%, is allowed to vary from 10% to 45% below prescription dose. As the dose deficit in the 1% subvolume bin increases further, it drives TCP and EUD rapidly down and can lead to a serious loss in TCP and EUD. Based on their study, a dose deficit to a 1% volume of the target that is larger than 20% of the prescription dose may lead to serious loss of TCP, even if a large volume of the target is boosted above the prescription dose, and hence, particular attention has to be paid to small-volume ?cold? regions in the target. Furthermore, we conclude that the effect of cold regions on TCP can be minimized if the EUD associated with the target DVH is constrained to be equal to or larger than that of the intended prescription dose. Preliminary investigation suggests that helical tomotherapy appears to achieve better homogeneity for complex tumor volumes than linac-based IMRT or 3D conformal radiation therapy planning (64). The avoidance of the potential consequences of ?hot? and ?cold? spots is being further explored specifically aiming to exploit the inherent advantages of helical tomotherapy.

Conclusions

Clinical implementation of IMRT, especially image-guided IMRT is in a state of rapid evolution. Helical tomotherapy, one the latest steps in this evolution, is an IMRT system whose design incorporates aspects such as infinite beam angle optimization and MVCT-based delivery verification. These features have the potential to permit the full clinical development of adaptive radiotherapy and conformal avoidance. To realize the ultimate goal of improving clinical outcomes for our patients, appropriate patient immobilization, optimized target localization, conformal avoidance of sensitive normal structures, and radiobiologically-guided dose escalation is required. The clinical implementation of helical tomotherapy, and the consequent issues raised (such as radiation dose-rates and dose homogeneity) present questions and opportunities that may change the current paradigm in radiation oncology.

Acknowledgements

This work was supported by NIH CA48902, NIH P01 CA088960.

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