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Proton, as well as other ion, beams applied by electro-magnetic deflection in pencil-beam scanning (PBS) are minimally perturbed and thus can be quantified a priori by their fundamental interactions in a medium. This a priori quantification permits an optimal reduction of characterizing measurements on a particular PBS delivery system. The combination of a priori quantification and measurements will then suffice to fully describe the physical interactions necessary for treatment planning purposes. We consider, for proton beams, these interactions and derive a 'Golden' beam data set. The Golden beam data set quantifies the pristine Bragg peak depth-dose distribution in terms of primary, multiple Coulomb scatter, and secondary, nuclear scatter, components. The set reduces the required measurements on a PBS delivery system to the measurement of energy spread and initial phase space as a function of energy. The depth doses are described in absolute units of Gy(RBE) mm² Gp⁻¹, where Gp equals 10⁹ (giga) protons, thus providing a direct mapping from treatment planning parameters to integrated beam current. We used these Golden beam data on our PBS delivery systems and demonstrated that they yield absolute dosimetry well within clinical tolerance.

Intensity modulated proton therapy (IMPT) implies the electromagnetic spatial control of well-circumscribed "pencil beams" of protons of variable energy and intensity. Proton pencil beams take advantage of the charged-particle Bragg peak-the characteristic peak of dose at the end of range-combined with the modulation of pencil beam variables to create target-local modulations in dose that achieves the dose objectives. IMPT improves on X-ray intensity modulated beams (intensity modulated radiotherapy or volumetric modulated arc therapy) with dose modulation along the beam axis as well as lateral, in-field, dose modulation. The clinical practice of IMPT further improves the healthy tissue vs target dose differential in comparison with X-rays and thus allows increased target dose with dose reduction elsewhere. In addition, heavy-charged-particle beams allow for the modulation of biological effects, which is of active interest in combination with dose "painting" within a target. The clinical utilization of IMPT is actively pursued but technical, physical and clinical questions remain. Technical questions pertain to control processes for manipulating pencil beams from the creation of the proton beam to delivery within the patient within the accuracy requirement. Physical questions pertain to the interplay between the proton penetration and variations between planned and actual patient anatomical representation and the intrinsic uncertainty in tissue stopping powers (the measure of energy loss per unit distance). Clinical questions remain concerning the impact and management of the technical and physical questions within the context of the daily treatment delivery, the clinical benefit of IMPT and the biological response differential compared with X-rays against which clinical benefit will be judged. It is expected that IMPT will replace other modes of proton field delivery. Proton radiotherapy, since its first practice 50 years ago, always required the highest level of accuracy and pioneered volumetric treatment planning and imaging at a level of quality now standard in X-ray therapy. IMPT requires not only the highest precision tools but also the highest level of system integration of the services required to deliver high-precision radiotherapy.

We present a method to include robustness into a multi-criteria optimization (MCO) framework for intensity-modulated proton therapy (IMPT). The approach allows one to simultaneously explore the trade-off between different objectives as well as the trade-off between robustness and nominal plan quality. In MCO, a database of plans each emphasizing different treatment planning objectives, is pre-computed to approximate the Pareto surface. An IMPT treatment plan that strikes the best balance between the different objectives can be selected by navigating on the Pareto surface. In our approach, robustness is integrated into MCO by adding robustified objectives and constraints to the MCO problem. Uncertainties of the robust problem are modeled by pre-calculated dose-influence matrices for a nominal scenario and a number of pre-defined error scenarios. A robustified objective represents the worst objective function value that can be realized for any of the error scenarios. The optimization method is based on a linear projection solver and is capable of handling large problem sizes resulting from a fine dose grid resolution, many scenarios, and a large number of proton pencil beams. A base-of-skull case is used to demonstrate the robust optimization method. It is demonstrated that the robust optimizationmethod reduces the sensitivity of the treatment plan to setup and range errors to a degree that is not achieved by a safety margin approach. A chordoma case is analyzed in more detail to demonstrate the involved tradeoffs between target underdose and brainstem sparing as well as robustness and nominal plan quality. The latter illustrates the advantage of MCO in the context of robust planning. For all cases examined, the robust optimization for each Pareto optimal plan takes less than 5 min on a standard computer, making a computationally friendly interface possible to the planner., Comment: 19 pages, 6 figures, to appear on Physics in medicine and biology

Purpose: In treatment planning for spot‐scanned intensity modulated proton therapy (IMPT), a fine‐grid pencil‐beam distribution is used to guarantee high‐quality treatment plans. This may lead to very large optimization problems with excessive planning times, especially for large target volumes. To improve the trade‐off between plan quality and optimization times, we have developed a new pencil‐beam placement method called ‘resampling’. Methods: Resampling is based on repeated multi‐criteria optimizations. In each iteration, a new sample of randomly placed pencil‐beams is optimized together with favorable (high‐weight) pencil‐beams of the previous solution. In previous studies, resampling was successfully applied for Cyber Knife plan optimization. In this study, IMPT resampling plans for four head‐and‐ neck cancer patients were compared with traditional IMPT plans, generated using a regular grid with typical spacing (5×5×4mm3). For resampling, sample sizes of 3000, 5000, 7000, and 9000 pencil‐beams per iteration were tested, storing the (intermediate) plans after each of in total 7 iterations. The same dose prescription and 3‐beam arrangement was used in all plans. Results: For similar optimization times and target coverage, resampling resulted in lower doses to organs‐at‐risk than the traditional approach. Mean doses were reduced by 0.4Gy on average (1.7%, range: 0Gy–0.9Gy) for both parotid glands, by 2.5Gy (7.1%, range 0.5Gy– 3.8Gy) for both submandibular glands and by 3.3Gy (9.6%, range: 2.3Gy–4Gy) for the swallowing muscles. Maximum doses to spinal cord and brain stem were on average reduced by 4.1Gy (25.7%, range: 2.3Gy–5.8Gy) and 3.4Gy (31.4%, range:−0.4Gy–9.5Gy), respectively. For comparable doses to organs‐at‐risk, optimization time was reduced by 38.7% on average (range: 6.7%–54.8%), being proportional to the target volume. Conclusions: Pencil‐beam resampling is an efficient method for IMPT plan optimization, allowing for clinically relevant improvements in plan quality and/or planning time, especially for large problem sizes. It opens possibilities for dealing with large‐scale problems such as beam‐angle optimization.

Purpose: Setup, range and anatomical uncertainties influence the dose delivered with proton pencil‐beams, but a quantification of these errors for intensity‐modulated proton therapy (IMPT) for oropharyngeal cancer is lacking. The purpose of this work is to quantify these effects. We also investigate whether treatment plans are more robust against errors when more beam directions are applied. Methods: We used an in‐house developed inverse treatment planning system for proton pencil‐beam scanning, which performs multi‐criteria optimization. First, treatment plans for 3, 5, and 7 beam directions were created for 5 oropharyngeal cancer patients. A simultaneous‐integrated boost technique was used, prescribing 66Gy and 54Gy to high and low dose regions, respectively, delivered in 30 fractions. Second, 300 treatment simulations were performed, recalculating the dose while including uncertainties. Anatomical uncertainties were taken into account by using two CT scans per patient. For setup errors an online setup‐protocol was simulated. DVH parameters were used for dose evaluation. Results: The treatment plans were of high quality, with good target coverage and excellent OAR sparing. However, setup, range and anatomical uncertainties can lead to large differences between the planned and delivered dose. For the 3‐beam plans, the expected V95% of the high‐ dose CTV reduced from 100% (planned) to on average 92%(range:82–98%), and the expected V107% increased from 1.3% (planned) to on average 4.2%(range:0.1%‐6.7%). The expected V95% of the low‐dose CTV reduced from 100% (planned) to on average 94% (range:86‐99%). The dose to the OARs generally increased. The plans with more beam directions were not more robust against errors (p>0.05). Conclusions: Setup, range and anatomical uncertainties in IMPT for oropharyngeal cancer patients can lead to considerable underdosage of the target volume, which should be accounted for by replanning and/or robust optimization techniques. Robustness is not achieved by increasing the number of beam directions included in the treatment plan.

Purpose: The delivery of post-mastectomy radiation therapy (PMRT) can be challenging for patients with left sided breast cancer that have undergone mastectomy. This study investigates the use of protons for PMRT in selected patients with unfavorable cardiac anatomy. We also report the first clinical application of protons for these patients. Methods and materials: Eleven patients were planned with protons, partially wide tangent photon fields (PWTF), and photon/electron (P/E) fields. Plans were generated with the goal of achieving 95% coverage of target volumes while maximally sparing cardiac and pulmonary structures. In addition, we report on two patients with unfavorable cardiac anatomy and IMN involvement that were treated with a mix of proton and standard radiation. Results: PWTF, P/E, and proton plans were generated and compared. Reasonable target volume coverage was achieved with PWTF and P/E fields, but proton therapy achieved superior coverage with a more homogeneous plan. Substantial cardiac and pulmonary sparing was achieved with proton therapy as compared to PWTF and P/E. In the two clinical cases, the delivery of proton radiation with a 7.2 to 9 Gy photon and electron component was feasible and well tolerated. Akimbo positioning was necessary for gantry clearance for one patient; the other was treated on a breast board with standard positioning (arms above her head). LAO field arrangement was used for both patients. Erythema and fatigue were the only noted side effects. Conclusions: Proton RT enables delivery of radiation to the chest wall and regional lymphatics, including the IMN, without compromise of coverage and with improved sparing of surrounding normal structures. This treatment is feasible, however, optimal patient set up may vary and field size is limited without multiple fields/matching.