Historically, proton therapy has been mainly and successfully

Physics Controversies in Proton Therapy Martijn Engelsman, PhD,* Marco Schwarz, PhD, and Lei Dong, PhD The physical characteristics of proton beams are appealing for cancer therapy. The rapid increase in operational and planned proton therapy facilities may suggest that this technology is a plug-and-play valuable addition to the arsenal of the radiation oncologist and medical physicist. In reality, the technology is still evolving, so planning and delivery of proton therapy in patients face many practical challenges. This review article discusses the current status of proton therapy treatment planning and delivery techniques, indicates current limitations in dealing with range uncertainties, and proposes possible developments for proton therapy and supplementary technology to try to realize the actual potential of proton therapy. Semin Radiat Oncol 23:88-96 2013 All rights reserved. *Delft University of Technology, Delft, The Netherlands. ATreP Agenzia Provinciale per la Protonterapia, Trento, Italy. Scripps Proton Therapy Center, San Diego, CA. All authors contributed equally to this manuscript. The authors declare no conflict of interest. Address reprint requests to Martijn Engelsman, PhD, Delft University of Technology, Delft, The Netherlands. E-mail: m.engelsman@tudelft.nl Historically, proton therapy has been mainly and successfully applied to what are now considered standard indications for this technique: ocular melanomas and intracranial tumors. This is partially due to technical limitations (eg, limited proton beam range) and partially because for these tumor sites, the treatment-related uncertainties are either well under control or small enough not to be limiting safe and effective application of proton therapy. Since the mid-nineties, there has been a rapid increase in both the worldwide availability of proton therapy technology and the indications that can be treated with this technology. Also recently, a shift from the standard method of passively scattered proton therapy, 1 through uniform scanning, 2 to modern pencilbeam scanning (PBS) technology 3 has commenced. The excitement about proton therapy can be understood by the dosimetric benefits often portrayed as in Figure 1. The obvious advantages are a much lower dose proximal to the tumor, and no dose a few centimeters distal to the tumor. This allows a reduction in integral dose to the patient of up to a factor of 3 and easy sparing of organs at risk that are located a few centimeters from the target. However, with the invention of intensity-modulated photon therapy (IMXT) and the use of a drastically increased number of beam angles, the advantage of standard proton therapy is not so obvious, with perhaps the exception of lower dose in the low-dose regions. Compared with standard proton therapy, PBS offers the advantage of further dose conformality, and it allows further sparing of organs at risk that are in the beam path. The increased skin dose for proton therapy is a known drawback complicating treatments of tumors that are not deep seated. Less widely realized is that it is difficult to achieve a lateral proton beam penumbra that is clearly advantageous compared with the penumbra of external beam photon therapy. 4 The values in Figure 2 are based on typical existing proton therapy equipment but should only be taken as an indication, as the exact values of proton beam penumbra depend heavily on beam-line optics and many other aspects, such as the distance of range shifters, apertures, or range compensators 5 with respect to the patient, and on whether apertures are used for low PBS energies. However, for sparing organs at risk that are in proximity to the target, the lateral penumbra of proton beams is not an advantage compared with photon beams. The distal proton penumbra is much sharper than the lateral penumbra, especially when using uniform scanning or PBS, and is typically approximately 3-5 mm. 6 However, as a consequence of range uncertainties, in current clinical practice, the distal fall-off is rarely used to spare an organ at risk that is in proximity (ie, 1-2 cm) to the target volume. The dashed lines in Figure 1 show that, because of range uncertainties, the finite range of proton beams is not only an advantage but also one of the main risks in proton therapy. Simulated for this dashed line is the presence of increaseddensity material in the beam path that was not present at the time of treatment planning. The photon depth dose profile is only minimally affected, whereas for the proton beam, this results in a dose difference between 0% and 100% to a rather large volume of target or, if the density variation is reversed, to an organ at risk that is distal to the 88 1053-4296/13/$-see front matter 2013 All rights reserved. http://dx.doi.org/10.1016/j.semradonc.2012.11.003

Physics controversies in proton therapy 89 Dose (%) 160 140 120 100 80 60 40 Increased density Photons 10MV Protons: Spread-out Bragg Peak Beam Direction 20 Protons: Pristine Bragg Peak 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Depth (cm) Figure 1 Depth dose curves without (solid line) and with (dashed) an anatomical density variation in the beam entrance region. (Color version of figure is available online.) target. There are many factors contributing to the cumulative uncertainty of the distal fall-off 7,8 even in the absence of anatomy variation. Especially for deep-seated targets such as in the pelvic region, an estimated uncertainty of approximately 1 cm is not uncommon. For photon therapy, exact localization and alignment of the tumor help guarantee a high-fidelity dose delivery. However, in proton therapy, target alignment is only a partial solution. Variation in patient anatomy anywhere in the beam path can lead to severe degradation of the actual delivered dose distribution compared with the treatment plan. Arguably a controversial statement, although often expressed, is that if the cost of treatment were equal, all patients would be treated with proton therapy, rather than IMXT. Clinical indications have already been discussed where current state-of-the-art proton therapy may not (yet) be able to offer a competitive advantage to IMXT or brachytherapy, such as stereotactic irradiation of peripheral lung lesions 9 or the treatment of (early-stage) prostate cancer. 10 The potential of proton therapy, owing to its inherent physics properties, to sculpt a 3-dimensional (3D) dose distribution and spare organs at risk is clear and is easily shown under physics reference conditions such as in a water tank (Fig. 1). However, effectively dealing with (range) uncertainties in treatment planning and treatment delivery of actual patient geometries, especially due to anatomical variation over time, is the biggest challenge in realizing the potential of proton therapy and in defining its ultimate role in radiotherapy. As it stands, the role of proton therapy may be exemplary for some cancer indications, but may remain only marginal for others. 11 The next sections of this article discuss physics aspects of proton therapy where further improvements are possible, or even required, and certainly envisioned to distinguish itself in reference to rapid developments in image-guidance and adaptive strategies in photon therapy. Range uncertainty is unique for particle beam therapy. The physics aspects discussed focus on limiting dose degradation due to unintended range variation. 30 Treatment Planning Owing to the finite range of protons, one should start from the assumption that even small positioning errors and changes in patient anatomy between treatment planning and treatment delivery can result in noticeable dose deformation. Imaging Computed tomography (CT) images are used to map the patient anatomy in terms of proton stopping power ratio properties. The accuracy in estimating the stopping power ratio from CT numbers is critical, and stoichiometric calibration 12 is typically used to minimize range uncertainties due to CT imaging. 13 This method has the advantage of not being affected by the differences in elemental composition between substitute material used in calibration and actual biological tissues. However, stoichiometric calibration does not eliminate the uncertainty in estimated stopping power ratios, 14 and imaging is not the only source of range uncertainty. 8 As a consequence, a distal margin of approximately 3% of the range is usually taken into account during planning. This uncertainty can perhaps be reduced using proton radiography, which is discussed in the image-guidance section. Proton Treatment Planning and Geometrical Uncertainties In photon therapy, the established tool to compensate for geometrical uncertainties is the planning target volume (PTV 15 ). The PTV, being (implicitly) based on the assumption that the dose distribution is shape invariant with respect to geometrical uncertainties, cannot be applied sic et simpliciter to protons. Proton therapy is still missing an equivalent of the PTV that, although not perfect, is good enough, simple enough, and commonly applied for both dose planning and dose reporting. For passively scattered proton therapy, the planning approach typically consists in (a) preferring beam directions that avoid (if possible) highly heterogeneous regions such as Figure 2 Lateral penumbra as a function of depth for a single photon beam, for a passively scattered (PSPT) proton beam, and for uncollimated proton pencil-beam scanning (PBS) with 2 different spot sizes (1 sigma). Please note that exact values depend on the beamline optics. Proton data based on Safai et al. 6 RC, range compensator thickness. (Color version of figure is available online.)

90 M. Engelsman, M. Schwarz, and L. Dong the nasal cavities, (b) applying a beam-specific additional distal and proximal margin to account for range uncertainties, (c) setting the beam apertures to allow for displacements of the target in the plane orthogonal to the beam direction, and (d) smearing the range compensator to account for the dosimetric effects of such lateral displacements. 16-18 Treatments with PBS delivering uniform target doses from each field can be planned in a similar way, that is, defining a beam-specific PTV the contour of which is such as to account for range uncertainties, lateral displacement, and its dosimetric effects. 19 The situation is more complicated with scattered patched fields and intensity-modulated proton therapy (IMPT), 20 where the dose distribution in the target is obtained by combining heterogeneous dose distributions from individual fields. In IMPT, the usefulness of a PTV is questionable at the least, as geometrical uncertainties can affect the dose distribution not only at the edges of the high-dose region but also within the clinical target volume. 21 Currently, this problem is tackled implicitly (some may say defensively), that is, IMPT and patched fields are applied only when strictly needed and in such a way as to mitigate the impact of range uncertainties and anatomy variation on the total dose distribution. This approach is understandable in the early days of a treatment technique, but in the longer term, better strategies, such as those mentioned later in the text, need to be implemented. Robustness in Plan Optimization In the context of treatment planning, robustness measures the difference in quality between planned and delivered dose distribution in presence of uncertainties in the input data (beam and patient model). A highly robust plan is one that shows little or no degradation of the plan quality between planning and delivery. The most satisfactory treatment planning solution to the problem of uncertainties is to explicitly account for them in the optimization cost function. Methods for robust optimization differ on how to incorporate range uncertainties and setup errors into the cost function, and constraints. Unkelbach et al 22 proposed robust optimization through probabilistic planning. In this setting, the range of each pencil beam is a random variable, and the quantity to be optimized is not a nominal dose distribution, but rather the expected residual cost over the possible values of range uncertainties and setup errors, each weighted according to its probability. Pflugfelder et al 23 suggested the worst-case optimization, which involves the following steps: (1) via the simulation of range uncertainties and positioning errors for each voxel, the worst-case dose is obtained; (2) the dose distribution composed of all worst-case voxels is then included in the cost function. This approach is computationally more efficient than probabilistic planning, but it has the disadvantage that the worst-case dose distribution may be unphysical. Plans generated with worst-case optimization may therefore be overly conservative. An alternative to worstcase optimization is minimax optimization, 24 where the correlation between uncertainties in different voxels is taken into account, and thus only physically realizable dose distributions are considered. Robustness in Plan Evaluation The transition from conventional to robust optimization is likely to take time. A pragmatic intermediate solution is to perform a robustness analysis on the final treatment plan. Existing treatment planning software typically presents dose distributions only on a static anatomy, although the plan may already incorporate some uncertainty concerns. Starting from plan robustness evaluation, rather than robustness optimization, has 3 advantages: 1. It is relevant regardless of the beam delivery technique. Scattered beam plans need robustness analysis as much as IMPT, for both plan evaluation and dose reporting. 2. Robustness evaluation can be coded quite simply in existing commercial treatment planning systems, unlike robust optimization, which requires a more significant software development. 3. The design of clinically relevant cost functions for robust optimization would benefit from extensive experience in evaluating plan robustness. The best way to visualize and evaluate plan robustness in clinical practice is still an unsolved problem. If multicriteria optimization becomes popular, one may consider robustness as an additional dimension the user is able to explore while choosing the best solution among competing plans. 25 It is worth noting that concerns on plan robustness thus far have had no impact on treatment planning studies comparing protons with photons. 26 Such studies are a popular, less complicated, and potentially useful way to compare treatment techniques, up to the point of enabling in silico trials. 27 Comparisons based on the same PTV for photons and protons are common nowadays, but they may systematically over- or underestimate the advantages of proton therapy. Planning studies should soon move, if not to robust optimization, at least to a comparison of dose distributions where the effects of geometrical uncertainties are quantified patient by patient for both techniques. Motion Management With anatomical variation between fractions and over the treatment course discussed in the section on adaptive radiotherapy, this section details the efforts toward mitigation of the dosimetric effects of (periodic) intrafractional anatomical variation. Table 1 provides a summary of motion effects and mitigation strategies. Dose blurring refers to the smoothing of dose gradients due to motion only as also described for photon therapy. 28 It is the smallest of the 3 effects. Anatomy variation means the fluctuation in proton beam range in the patient due to, for example, the diaphragm moving into the beam path. 29 Finally, the interplay effect 30 relates to interference between the uniform scanning or PBS time structure and motion of target

Physics controversies in proton therapy 91 Table 1 Effects of Motion on the Proton Therapy Dose Distribution (Columns) and Strategies to Address These (Rows) Dose Blurring Dose Deformation Due to Anatomy Variation Interplay Effect Margins ** * * Minimize motion *** *** *** Rescanning * ** ** Tracking *** *** *** Robust planning ** ** * The effectiveness of the strategies is scored from * (worst) to *** (best). The details and remaining difficulties of the strategies will be discussed in the text. and organs at risk. Effectively dealing with all 3 effects in a routine clinical setting has not yet been achieved. Margins The margining approaches such as described by Engelsman et al 18 and Kang et al 31 are aimed at providing a forward planning approach mimicking traditional planning as much as possible. The applied margins, either by smearing or density override, are generous such that target coverage is virtually assured even under considerable anatomical variations. However, this means that sparing of organs at risk is suboptimal. Dose blurring is not mitigated but addressed by increasing the lateral safety margins, and the margin approach does not address the interplay effect. The margining approach is unsatisfying in that a generalized approach is used although motion patterns and related density variations are highly patient-specific. Clinical judgment as to the adequacy of patient-individual treatment plans in the presence of organ motion and setup uncertainty could certainly benefit from improved 4D dose-accumulation tools being readily available in treatment planning systems. Minimize Motion Minimizing motion is perhaps the universal approach to mitigate motion-related issues. Strategies to freeze target motion vary from voluntary breath hold, through gating, 32 to apnea using anesthesia. 33 They can be adopted from photon experience and as such are readily available for proton therapy. However, patient comfort is compromised, and the dosimetric effects of residual motion (eg, in the gating window) still need to be addressed by margins and/or rescanning. Furthermore, these strategies are usually based on triggering the beam using a motion surrogate (eg, an external marker) as opposed to the motion of internal anatomy. As such, they may introduce small but significant systematic anatomical variations, not only in the tumor position but, more importantly, in the entire anatomical geometry. These anatomical variations require advanced volumetric imaging to be properly addressed (see the section on image-guidance and adaptive radiation therapy later in the text). Rescanning Rescanning addresses the interplay effect by delivery of a single field dose in multiple repaints. Many parameters can be tweaked, 34-36 and a single best approach has not been established, certainly not over all cancer indications. However, it has been shown that it is beneficial for the rescanning strategy to take the breathing phase explicitly into account, 37,38 thereby putting extra demands on the coupling of online motion monitoring and the proton therapy delivery system. Multiple rescans help average out the dosimetric consequences of anatomical density variations, at the cost of a dose-smearing effect. Such averaging can also be achieved implicitly by increasing the number of beam directions 39 or explicitly by increasing the overlap between PBS spots. 40 It still has to be proven in routine clinical practice that rescanning can be delivered fast and effectively enough such that the interplay effect is not a distinguishing factor between standard proton therapy and the scanned modalities (uniform scanning and PBS). Tracking In beam tracking, the 3D position of each pencil beam is adjusted to the real-time variation in patient geometry. This allows the patient to breath freely, maximizes the dose delivery efficiency, and addresses the problem of motion at its core. Technical demands on, and required control over, the treatment planning system, real-time 3D motion monitoring, and the treatment delivery system are substantial, limiting the pursuit of clinical implementation at the moment to only a limited number of institutes. Robust Planning In principle, robust planning can mitigate the effects of anatomy variation and even of interplay. However, it has not yet been applied for this purpose. For further details, please refer to the section on treatment planning earlier in the text. Clinical Outlook Strategies for proton therapy to deal with intrafractional motion are addressed in more than 50 studies, of which a comprehensive overview is provided by Bert et al. 35 This stresses both the difficulty of the topic and the importance it has in the particle therapy community. Minimizing motion is the easiest to implement clinically, and if combined with adaptive radiation therapy to counter more gradual anatomy variations, it can be an effective strategy. Application of the other strategies (such as repainting and tracking) can increase treatment accuracy, patient comfort, or patient throughput. However, for the next few years, their application will, or perhaps should, be limited to those facilities that have (developed) 4D dose error simulation platforms and that have a more direct control over the treatment delivery system than allowed by current commercial solutions.

92 M. Engelsman, M. Schwarz, and L. Dong Image-Guidance and Adaptive Radiation Therapy Orthogonal kilovoltage (kv) based image-guidance techniques have been used in charged-particle therapy routinely from the beginning in all proton therapy centers, 41 whereas most photon therapy centers were still using megavoltage portal imaging for patient position verification in the early 90s. One important reason is that, as therapeutic charged particles stop in the patient, portal imaging using the treatment beam is not feasible. 42 After an initial advantage, proton therapy over the past 5-10 years has been trailing the rapid development and adoption of newer image-guidance technologies in photon therapy. Most existing charged-particle therapy facilities were designed at least 10 years ago, when commercial cone-beam CT (CBCT)-based volumetric imaging did not exist. Therefore, the current standard for image guidance in proton therapy is still the stereoscopic kv x-ray imaging technique, whereas most modern photon therapy centers use CBCT-based image-guided radiation therapy (IGRT) technology. The major challenge in 2D-2D stereoscopic x-ray imaging technique is the difficulty to detect the soft-tissue target itself with its complete shape and orientation. The projection ambiguity in limited views can lead to a large target localization error. The development of 2D-3D image registration algorithms can mitigate some of these uncertainties by taking advantage of the planning CT. 43,44 Using this 2D-3D image registration technique, out-of-plane rotations and translational shifts can be simultaneously identified with the bestmatching digitally reconstructed radiographs. Unfortunately, few proton therapy centers are using this 2D-3D image registration approach. More importantly, target alignment based on 2D imaging does not address the much needed validation of proton range (ie, patient anatomy variation anywhere in the beam path) for the image-guidance process. This requirement can be perhaps more adequately described as dose-guided setup. Patient external body contour can vary on a daily basis, and there may be daily changes in the immobilization device and internal anatomy variations in the beam path, each affecting proton range. Some IGRT Technologies May Be Insufficient for Proton Therapy Most existing IGRT technologies focus on target alignment either directly or indirectly using target surrogates. Technologies such as orthogonal x-ray imaging use bony landmarks to align the target. In some situations, bony landmarks may not be a good surrogate for the treatment target, for example, in prostate cancer. Implanted fiducials may be used in proton therapy. The use of high-density metallic fiducials may introduce metal artifacts that can introduce additional uncertainties owing to their CT artifacts, and they could influence the dose distribution. However, most importantly, fiducial markers only represent the position of the target. It will not monitor the tissue change, and variation in water-equivalent thickness, in the beam path elsewhere outside the target. Volumetric imaging techniques, such as (in-room) CT or CBCT, are the preferred IGRT approach for proton therapy. Because of inaccuracies in their CT numbers, CBCT images may not necessarily allow direct dose recalculation and replanning, but they will allow validation of much of the entire patient geometry. As such, it can play a valuable role in decision protocols for treatment adaptation. The ultimate method for in-room imaging may well be proton radiography 45,46 or even proton CT. 47,48 Especially, the latter would not only provide the volumetric patient geometry at isocenter, it would also provide a direct measurement of proton attenuation in the patient, thereby reducing range uncertainty. One major technical difficulty is that the numerous small-angle scatterings due to Coulomb interactions along the beam path pose an inherent limit on the spatial resolution of the acquired images. 49,50 Both proton radiography and proton CT are far from ready for routine clinical applications, and their use for all body sites requires higher proton energies than those currently available. Impact of Anatomical Changes and Adaptive Radiotherapy It is not surprising that almost all future proton therapy centers have planned CBCT or (in-room) CT imaging capability. There is a growing body of literature reporting data on interand intrafractional variations and tumor shrinkage. 51-54 For proton therapy, such changes in internal anatomy could introduce noteworthy shift and distortion of the dose distribution even if an image-guided setup has been performed properly. Some of these large anatomical changes discovered during routine IGRT procedures will prompt dosimetric evaluation, which can subsequently lead to replanning, that is, adaptive radiotherapy. Adaptive radiation therapy can correct the dosimetric effect of nonrigid anatomical changes, thereby minimizing the dosimetric effect of applying a treatment plan to a geometry for which it was not designed. Figure 3 shows an example of a lung cancer proton therapy plan, which was reevaluated in weekly 4D CT scans. The fourth-week CT showed a significant change in the tumor volume, which resulted in overshoot of dose into the contralateral lung. A new plan was designed to repair the suboptimal dose distribution and applied for the following week. This is an example of the application of offline adaptive radiation therapy. The common triggers for replanning are (1) nonrigid normal anatomy changes that cannot be corrected by repositioning the treatment couch in an IGRT procedure, and (2) significant changes in tumor volume or the density of the volume. The need for dose-guided adaptive therapy is more important for proton therapy, in general, and increases even further now that more and more tumors in the thoracic and abdominal regions are targeted. The timing of CT assessment and the frequency of replanning are still considered an evolving topic. However, because of the larger dosimetric impact of anatomical variations, it is likely that the frequency of

Physics controversies in proton therapy 93 Figure 3 An example of offline adaptive proton therapy. Owing to tumor shrinkage and opening of an air cavity, proton beams penetrated more into the contralateral lung and posterior tissue in the fourth week of treatment (left figure). An adaptive plan (shown to the right) was designed to repair the suboptimal dose distribution in the original plan (not shown) and applied for the rest of treatment fractions. reimaging and plan adaptation will be higher for proton therapy than for photon therapy. Other than the lack of availability of (in-room) volumetric imaging, the frequency of treatment adaptation is mainly limited by the time and resources required. Most, if not all, currently available treatment planning systems, oncology information systems, and beam time for quality assurance procedures do not allow the smooth and effective application of adaptive radiation therapy. In the mean time, the proton therapy community should focus on the design and publication of practical treatment-adaptation protocols on a per-site basis. Treatment Monitoring Because the sharp distal fall-off of a proton beam is sensitive to range uncertainty, it may be desirable to confirm or even monitor the dose delivery in or near real time during patient treatment. Taking advantage of proton interactions with human tissue, various secondary particles generated in the nuclear interaction can be detected to reconstruct the original proton beam path inside the patient. The use of positron emission tomography imaging to detect positrons generated by therapeutic proton beam was studied by Parodi et al 55,56 and other investigators. 57,58 Unfortunately, for obtaining maximum information, the PET verification method also requires an accurate Monte Carlo simulation method to predict the expected activity to compare with the measured activity. The general consensus is that PET range verification is more accurate in bony tissues than in soft tissues, in which the biological washout is more pronounced. The measured positron distribution may therefore not accurately represent the distribution of proton initiated reactions. An alternative technique is to measure the prompt -rays that are emitted immediately (within 10 19-10 9 s) after the proton interaction with nuclei of the patient s tissue. The prompt -rays have a wide spectrum, with a few characteristic rays of nuclei, which could be used for detecting the location of the proton beam. 59-62 All these in vivo detection and monitoring systems are under active research. It is unknown whether these methods are accurate enough to reduce the margin requirement in actual patient treatment. In addition to (near) real-time monitoring, posttreatment verification may be useful to confirm the accuracy of treatment delivery in the patient. Magnetic resonance imaging signal change in the vertebral bone marrow undergoing fatty replacement after proton therapy has been used to confirm a range variation between 0.8 and 3.1 mm. 63 Similar results are also obtained with PET image reconstruction immediately after prostate cancer proton therapy. 57 These in vivo studies are useful to confirm whether adequate range uncertainty has been incorporated in the planning margin. Future Role of Proton Beam Delivery Techniques Nowadays, proton treatments are delivered with either passively scattered, uniform scanning, or PBS techniques. The existence of three delivery techniques suggests, on the one hand, an evolving field and, on the other hand, that none of these methods is clearly superior to the others for every clinical indication. Some relevant properties of these techniques as available now in commercial proton therapy systems are summarized in Table 2. Passively Scattered Proton Therapy Passive scattering 2 represents both the past and a large share of present-day proton therapy. Thus far, virtually all published clinical results of proton therapy are from this standard delivery technique. The main advantage over uniform scanning and PBS are faster energy changes between neighboring layers. With passive scattering, the whole field is delivered nearly instantaneously, such that interplay effects play no

94 M. Engelsman, M. Schwarz, and L. Dong Table 2 Qualitative Comparison Between Proton Beam Delivery Techniques Passive Scattering Uniform Scanning Pencil-Beam Scanning Flexibility in shaping the dose distribution ** ** *** Dose conformity ** ** *** No/reduced need for patient-specific hardware * * *** Speed in energy changes *** * * Speed in overall dose delivery *** ** ** Ease of commissioning * ** ** Maturity of the technique *** ** * The properties are scored from * (worst) to *** (best). For a short discussion on beam penumbra, please refer to the introductory section of this article. role with regard to dose deformation. This, combined with speed in overall dose delivery, probably makes it the most reliable proton delivery technique available today for challenging indications such as lung cancer. Perhaps counterintuitively, passive scattering has a certain small advantage in treatment planning, given the immature stage of planning for PBS: designing proton treatment plans for the passive scattering technique may be time-consuming, but the forward planning process allows a skilled planner to control the beam parameters affecting robustness (eg, patch lines) more explicitly than in PBS or IMPT. Direct visualization of cause and effect of planning decisions provides comfort in adopting the relatively new technology that proton therapy is for many centers. Unfortunately, the inherent limitations of the passive scattering technique, such as the need for patient-specific hardware, affect clinical efficiency. The lack of proximal conformity, severe restrictions to dose modulation capabilities, and extensive commissioning time are such that this technique is not going to significantly improve in the near future, and in the longer term, will likely be abandoned. Uniform Scanning Uniform scanning is in many ways a hybrid between passive scattering and the more advanced PBS. The dose distributions properties are the same as in passive scattering, but they are obtained on a somewhat simpler system, thus facilitating clinical commissioning. Although PBS techniques are maturing, uniform scanning is a good option for a new proton therapy center, in that it may start its activity in a relatively short time using planning techniques and delivering dose distributions that do not depart from previous clinical experience of proton therapy. In uniform scanning, there is almost no need for scattering material to broaden the beam, thus allowing a (slightly) higher maximum range than in passive scattering. The question whether the slower energy changes of uniform scanning may create noticeable interplay effects has not been answered yet. In the longer term, uniform scanning is unlikely to be the dominant delivery technique, as its dose distributions suffer from the same problems as passive scattering: a lack of dose modulation within the field and of proximal target dose conformity. For the high-dose region, this may result in worse dosimetric results than state-of theart IMXT. Uniform scanning also requires field-specific hardware, thereby limiting treatment efficiency. Pencil-Beam Scanning The first clinical application of PBS in proton therapy is more than 10 years old, 64 and the technique is often taken for granted. Truth is that currently only a small fraction of patients receiving proton therapy is treated with PBS, and an even smaller fraction with IMPT. 20 It is unclear whether this is solely due to the slow technological development of PBS or whether this is an indication that for many clinical indications, IMPT is, so to speak, an overkill with respect to the needs of clinical practice. There are reasons to favor the first hypothesis. If proton therapy cannot deliver dose distributions better than or equal to advanced photon techniques such as IMXT over the whole dose range, assessing the (cost) benefits of protons versus photons will be even more difficult than it already is. Passive scattering and uniform scanning are superior to IMXT dose distributions in the medium-to-low dose range, 27 but it is not obvious that they can match the dose conformity and homogeneity of current IMXT techniques. Although the results of planning comparisons between IMXT and proton therapy are subject to methodological problems, some suggest that PBS with small beam size ( 5 mm sigma) is needed to create proton dose distributions comparable with the best of IMXT. 65 Such small beam sizes can be obtained in recent delivery systems for energies 70-100 MeV. At lower energies, the beam size is typically 5 mm, and a range shifter is often used. If good conformality is needed at shallow depths, one should therefore consider the use of an aperture to sharpen the lateral penumbra and/or the need of minimizing the air gap between patient and range shifter. Either need would significantly affect the clinical workflow and reduce the operational advantages of PBS over passive scattering. Therefore, we think that proton therapy is in urgent need of technologically mature PBS solutions, both in planning and in beam delivery, for PBS to quickly become the default proton technique, at least for nonmoving tumors. We are still a few years away from reaching this goal. Conclusions Proton therapy has a tremendous potential that is easily shown under physics reference conditions such as a water tank. However, in many important aspects (image guidance, workflow, etc), it is not yet a mature therapy when it comes to

Physics controversies in proton therapy 95 dealing with treatment-related uncertainties in patients, especially those uncertainties affecting the proton range. In the next 3-5 years, the proton therapy community will rapidly roll out both PBS and (in-room) volumetric imaging, thereby providing two important ingredients toward (online) adaptive therapy. What is also needed is commercial treatment planning technology (ie, 4D dose error simulation platforms) smoothly integrated into the treatment design and delivery workflow, such that the proper mix between range uncertainty and range variation countermeasures (eg, robust optimization, patient motion control, treatment plan adaptation, etc) can be chosen and applied at the level of the specific tumor site, or even at the level of the individual patient. In addition, improvements in dose calculation accuracy, especially in heterogeneous tissues, and in pencil-beam spot size are necessary. Until all these conditions are met, it will not be possible for everyone to apply best-possible proton therapy to every cancer indication. More realistically, proton therapy may ultimately have a clinical benefit for a subset of cancer patients, with the exact subset not yet known. Numerous improvements in proton therapy delivery technology and in integration into the clinical workflow of complementary technology are necessary before proton therapy reaches its maximum potential for many cancer patients. References 1. Koehler AM, Schneider RJ, Sisterson JM: Flattening of proton dose distributions for large-field radiotherapy. Med Phys 4:297-301, 1977 2. Fujitaka S, Takayanagi T, Fujimoto R, et al: Reduction of the number of stacking layers in proton uniform scanning. Phys Med Biol 54:3101-3111, 2009 3. Blattmann H, Coray A, Pedroni E, et al: Spot scanning for 250 MeV protons. Strahlenther Onkol 166:45-48, 1990 4. 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