Methodologies in the modeling of combined chemo-radiation treatments.

The variety of treatment options for cancer patients has increased significantly in recent years. Not only do we combine radiation with surgery and chemotherapy, new therapeutic approaches such as immunotherapy and targeted therapies are starting to play a bigger role. Physics has made significant contributions to radiation therapy treatment planning and delivery. In particular, treatment plan optimization using inverse planning techniques has improved dose conformity considerably. Furthermore, medical physics is often the driving force behind tumor control and normal tissue complication modeling. While treatment optimization and outcome modeling does focus mainly on the effects of radiation, treatment modalities such as chemotherapy are treated independently or are even neglected entirely. This review summarizes the published efforts to model combined modality treatments combining radiation and chemotherapy. These models will play an increasing role in optimizing cancer therapy not only from a radiation and drug dosage standpoint, but also in terms of spatial and temporal optimization of treatment schedules.

Intensity modulated proton therapy.

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.

Characterizing a proton beam scanning system for Monte Carlo dose calculation in patients.

The presented work has two goals. First, to demonstrate the feasibility of accurately characterizing a proton radiation field at treatment head exit for Monte Carlo dose calculation of active scanning patient treatments. Second, to show that this characterization can be done based on measured depth dose curves and spot size alone, without consideration of the exact treatment head delivery system. This is demonstrated through calibration of a Monte Carlo code to the specific beam lines of two institutions, Massachusetts General Hospital (MGH) and Paul Scherrer Institute (PSI). Comparison of simulations modeling the full treatment head at MGH to ones employing a parameterized phase space of protons at treatment head exit reveals the adequacy of the method for patient simulations. The secondary particle production in the treatment head is typically below 0.2% of primary fluence, except for low-energy electrons (<0.6 MeV for 230 MeV protons), whose contribution to skin dose is negligible. However, there is significant difference between the two methods in the low-dose penumbra, making full treatment head simulations necessary to study out-of-field effects such as secondary cancer induction. To calibrate the Monte Carlo code to measurements in a water phantom, we use an analytical Bragg peak model to extract the range-dependent energy spread at the two institutions, as this quantity is usually not available through measurements. Comparison of the measured with the simulated depth dose curves demonstrates agreement within 0.5 mm over the entire energy range. Subsequently, we simulate three patient treatments with varying anatomical complexity (liver, head and neck and lung) to give an example how this approach can be employed to investigate site-specific discrepancies between treatment planning system and Monte Carlo simulations.

Site-specific range uncertainties caused by dose calculation algorithms for proton therapy.

The purpose of this study was to assess the possibility of introducing site-specific range margins to replace current generic margins in proton therapy. Further, the goal was to study the potential of reducing margins with current analytical dose calculations methods. For this purpose we investigate the impact of complex patient geometries on the capability of analytical dose calculation algorithms to accurately predict the range of proton fields. Dose distributions predicted by an analytical pencil-beam algorithm were compared with those obtained using Monte Carlo (MC) simulations (TOPAS). A total of 508 passively scattered treatment fields were analyzed for seven disease sites (liver, prostate, breast, medulloblastoma-spine, medulloblastoma-whole brain, lung and head and neck). Voxel-by-voxel comparisons were performed on two-dimensional distal dose surfaces calculated by pencil-beam and MC algorithms to obtain the average range differences and root mean square deviation for each field for the distal position of the 90% dose level (R90) and the 50% dose level (R50). The average dose degradation of the distal falloff region, defined as the distance between the distal position of the 80% and 20% dose levels (R80-R20), was also analyzed. All ranges were calculated in water-equivalent distances. Considering total range uncertainties and uncertainties from dose calculation alone, we were able to deduce site-specific estimations. For liver, prostate and whole brain fields our results demonstrate that a reduction of currently used uncertainty margins is feasible even without introducing MC dose calculations. We recommend range margins of 2.8% + 1.2 mm for liver and prostate treatments and 3.1% + 1.2 mm for whole brain treatments, respectively. On the other hand, current margins seem to be insufficient for some breast, lung and head and neck patients, at least if used generically. If no case specific adjustments are applied, a generic margin of 6.3% + 1.2 mm would be needed for breast, lung and head and neck treatments. We conclude that the currently used generic range uncertainty margins in proton therapy should be redefined site specific and that complex geometries may require a field specific adjustment. Routine verifications of treatment plans using MC simulations are recommended for patients with heterogeneous geometries.

Interplay effects in proton scanning for lung: a 4D Monte Carlo study assessing the impact of tumor and beam delivery parameters.

Relative motion between a tumor and a scanning proton beam results in a degradation of the dose distribution (interplay effect). This study investigates the relationship between beam scanning parameters and the interplay effect, with the goal of finding parameters that minimize interplay. 4D Monte Carlo simulations of pencil beam scanning proton therapy treatments were performed using the 4DCT geometry of five lung cancer patients of varying tumor size (50.4-167.1 cc) and motion amplitude (2.9-30.1 mm). Treatments were planned assuming delivery in 35 × 2.5 Gy(RBE) fractions. The spot size, time to change the beam energy (τes), time required for magnet settling (τss), initial breathing phase, spot spacing, scanning direction, scanning speed, beam current and patient breathing period were varied for each of the five patients. Simulations were performed for a single fraction and an approximation of conventional fractionation. For the patients considered, the interplay effect could not be predicted using the superior-inferior motion amplitude alone. Larger spot sizes (σ ~ 9-16 mm) were less susceptible to interplay, giving an equivalent uniform dose (EUD) of 99.0 ± 4.4% (1 standard deviation) in a single fraction compared to 86.1 ± 13.1% for smaller spots (σ ~ 2-4 mm). The smaller spot sizes gave EUD values as low as 65.3% of the prescription dose in a single fraction. Reducing the spot spacing improved the target dose homogeneity. The initial breathing phase can have a significant effect on the interplay, particularly for shorter delivery times. No clear benefit was evident when scanning either parallel or perpendicular to the predominant axis of motion. Longer breathing periods decreased the EUD. In general, longer delivery times led to lower interplay effects. Conventional fractionation showed significant improvement in terms of interplay, giving a EUD of at least 84.7% and 100.0% of the prescription dose for the small and larger spot sizes respectively. The interplay effect is highly patient specific, depending on the motion amplitude, tumor location and the delivery parameters. Large degradations of the dose distribution in a single fraction were observed, but improved significantly using conventional fractionation.

SU-E-T-500: Pencil-Beam versus Monte Carlo Based Dose Calculation for Proton Therapy Patients with Complex Geometries. Clinical Use of the TOPAS Monte Carlo System.

PURPOSE: To investigate the necessity of the verification of dose distributions using Monte Carlo (MC) simulations for proton therapy of head and neck patients and other complex patient geometries. METHODS: TOPAS, a TOol for PArticle Simulations that makes MC simulations easy-to-use for research and clinical use and is layered on top of Geant4, has been used to simulate the treatments of head and neck patients at the Massachusetts General Hospital (MGH). The resulting dose distributions have been compared to pencil beam calculations based on the XiO treatment planning system. Dose difference distributions were used to highlight areas where the two algorithms did not agree. Dose volume histograms are utilized to investigate the overall agreement of the planned doses in target structures. RESULTS: 21 head and neck patients, both nasopharynx and spinal cord, were investigated. The field complexity ranges from a single field up to 13 fields. For all patients, the dose in the clinical target volume agrees well. Nevertheless, differences in critical structures around the targets have been observed mostly due to range differences between the two algorithms. CONCLUSIONS: Pencil beam algorithms provide an accurate description of dose in the target volume. However, we conclude that the differences between MC simulations and pencil beam algorithms in regions outside the target for complex geometries, such as present in head and neck patients, support the necessity of routine use of MC simulations for treatment verifications before treatment. TOPAS is aiming to make such routine simulations available to all researchers and clinics. An automated interface utilizing TOPAS to enable such simulations has been developed at MGH and should become routinely used in the near future for patients with complex geometries. NIH/NCI R01 CA140735.

SU-E-T-552: Maximizing the Biological Effect of Proton Dose Delivered with Scanned Beam.

PURPOSE: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and controlled distribution of proton's linear energy transfer (LET). We evaluate potential gain in therapeutic effect from delivery of daily inhomogeneous fractional dose distributions in pencil beam scanning proton therapy (PBS-PT). METHODS: For cases of prostate cancer, we considered a hypofractionated course of 20 fractions of 3 Gy (assuming α/ß=1.5, the equivalent dose in 2-Gy fractions (ED2Gy) is 77.1 Gy). Two sets of dose distributions were planned using two opposed lateral fields to deliver a uniform dose: (1) in full-target plans (FTP) each beam targeted the entire gland (2) in split-target plans (STP), beams targeted only the respective proximal hemispheres (prostate split sagittally). Linear combinations of optimized beam intensity maps from FTP and STP, for a variety of mixing weights, were used to evaluate inhomogeneous fractional dose (IFD) distributions. IFD delivered doses boosting either hemisphere in alternating fractions, e.g., alternating between 40% and 160% of the nominal fractional dose (1.2-4.8 Gy). The equivalent uniform dose (EUD) was calculated for ED2Gy distributions. IFD plans were rescaled so that the EUD of rectum and bladder did not increase. LET distributions were calculated with Monte Carlo, and compared for different plans. RESULTS: In the IFD courses, the whole prostate received a nearly uniform dose in every 2 fractions, however EUD was higher than in conventional FTP by up to 8%. Rectal EUD decreased by 2%, and bladder EUD was unchanged. The LET distributions of FTP and STP were distinctly different, thus, in IFD, LET depended strongly on the mixing weights. CONCLUSIONS: In PBS-PT, modestly improved therapeutic outcome can be expected with delivery of inhomogeneous daily dose distributions, while administering the prescribed dose to target over the entire course. The biological effectiveness may be further enhanced by optimizing the LET distributions. The project was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center.

Elevated LET components in clinical proton beams.

This paper assesses the contribution of secondary particles to pencil and passively scattered proton beams, in particular when considering the dose-averaged linear energy transfer (LET(d)) in biological treatment planning. Proton Monte Carlo simulations are performed in water phantoms and for two patients, considering all primary and secondary particles, including recoils from inelastic nuclear interactions. Our results show that secondary protons exhibit LET(d) values up to a factor 10 higher than those of the primary protons at the same depth. Thus, secondary protons have a significant impact on the LET(d). Their contribution increases the LET(d) by ∼50% along the central axis and even >200% in the penumbra. Furthermore, the LET maximum after the peak changes from 12 to 15 keV µm(-1) when adding secondary protons to the primary contribution. This is important when modeling LET(d) with analytical methods. The contribution of recoils (A > 3) is observed to be 1.2% in the entrance region considering a prostate case. The degree of biological damage inflicted by recoils remains hard to quantify, but is discussed on the basis of detailed energy spectra. The results highlight the role of secondary protons in LET-based radiobiological effectiveness calculations for proton therapy and when analyzing radiobiological experiments. Furthermore, the findings demonstrate the impact of inhomogeneities on the LET and the subtle changes between the LET distributions of passively scattered and actively scanned beams.