Can We Advance Proton Therapy for Prostate? Considering Alternative Beam Angles and Relative Biological Effectiveness Variations When Comparing Against Intensity Modulated Radiation Therapy.

PURPOSE: For prostate treatments, robust evidence regarding the superiority of either intensity modulated radiation therapy (IMRT) or proton therapy is currently lacking. In this study we investigated the circumstances under which proton therapy should be expected to outperform IMRT, particularly the proton beam orientations and relative biological effectiveness (RBE) assumptions. METHODS AND MATERIALS: For 8 patients, 4 treatment planning strategies were considered: (A) IMRT; (B) passively scattered standard bilateral (SB) proton beams; (C) passively scattered anterior oblique (AO) proton beams, and (D) AO intensity modulated proton therapy (IMPT). For modalities (B)-(D) the dose and linear energy transfer (LET) distributions were simulated using the TOPAS Monte Carlo platform and RBE was calculated according to 3 different models. RESULTS: Assuming a fixed RBE of 1.1, our implementation of IMRT outperformed SB proton therapy across most normal tissue metrics. For the scattered AO proton plans, application of the variable RBE models resulted in substantial hotspots in rectal RBE weighted dose. For AO IMPT, it was typically not possible to find a plan that simultaneously met the tumor and rectal constraints for both fixed and variable RBE models. CONCLUSION: If either a fixed RBE of 1.1 or a variable RBE model could be validated in vivo, then it would always be possible to use AO IMPT to dose-boost the prostate and improve normal tissue sparing relative to IMRT. For a cohort without rectum spacer gels, this study (1) underlines the importance of resolving the question of proton RBE within the framework of an IMRT versus proton debate for the prostate and (2) highlights that without further LET/RBE model validation, great care must be taken if AO proton fields are to be considered for prostate treatments.

Dose assessment for the fetus considering scattered and secondary radiation from photon and proton therapy when treating a brain tumor of the mother.

The goal of this work was to determine the scattered photon dose and secondary neutron dose and resulting risk for the sensitive fetus from photon and proton radiotherapy when treating a brain tumor during pregnancy. Anthropomorphic pregnancy phantoms with three stages (3-, 6-, 9-month) based on ICRP reference parameters were implemented in Monte Carlo platform TOPAS, to evaluate the scattered dose and secondary neutron dose and dose equivalent. To evaluate the dose equivalent, dose averaged quality factors were considered for neutrons. This study compared three treatment modalities: passive scattering and pencil beam scanning proton therapy (PPT and PBS) and 6-MV 3D conformal photon therapy. The results show that, for 3D conformal photon therapy, the scattered photon dose equivalent to the fetal body increases from 0.011 to 0.030 mSv per treatment Gy with increasing stage of gestation. For PBS, the neutron dose equivalent to the fetal body was significantly lower, i.e. increasing from 1.5 × 10(-3) to 2.5 × 10(-3) mSv per treatment Gy with increasing stage of gestation. For PPT, the neutron dose equivalent of the fetus decreases from 0.17 to 0.13 mSv per treatment Gy with the growing fetus. The ratios of dose equivalents to the fetus for a 52.2 Gy(RBE) course of radiation therapy to a typical CT scan of the mother's head ranged from 3.4-4.4 for PBS, 30-41 for 3D conformal photon therapy and 180-500 for PPT, respectively. The attained dose to a fetus from the three modalities is far lower than the thresholds of malformation, severe mental retardation and lethal death. The childhood cancer excessive absolute risk was estimated using a linear no-threshold dose-response relationship. The risk would be 1.0 (95% CI: 0.6, 1.6) and 0.1 (95% CI: -0.01, 0.52) in 10(5) for the 9-month fetus for PBS with a prescribed dose of 52.2 Gy(RBE). The increased risks for PPT and photon therapy are about two and one orders of magnitude larger than that for PBS, respectively. We can conclude that a pregnant woman with a brain tumor could be treated with pencil beam scanning with acceptable risks to the fetus.

Assessing the Clinical Impact of Approximations in Analytical Dose Calculations for Proton Therapy.

PURPOSE: To assess the impact of approximations in current analytical dose calculation methods (ADCs) on tumor control probability (TCP) in proton therapy. METHODS: Dose distributions planned with ADC were compared with delivered dose distributions as determined by Monte Carlo simulations. A total of 50 patients were investigated in this analysis with 10 patients per site for 5 treatment sites (head and neck, lung, breast, prostate, liver). Differences were evaluated using dosimetric indices based on a dose-volume histogram analysis, a γ-index analysis, and estimations of TCP. RESULTS: We found that ADC overestimated the target doses on average by 1% to 2% for all patients considered. The mean dose, D95, D50, and D02 (the dose value covering 95%, 50% and 2% of the target volume, respectively) were predicted within 5% of the delivered dose. The γ-index passing rate for target volumes was above 96% for a 3%/3 mm criterion. Differences in TCP were up to 2%, 2.5%, 6%, 6.5%, and 11% for liver and breast, prostate, head and neck, and lung patients, respectively. Differences in normal tissue complication probabilities for bladder and anterior rectum of prostate patients were less than 3%. CONCLUSION: Our results indicate that current dose calculation algorithms lead to underdosage of the target by as much as 5%, resulting in differences in TCP of up to 11%. To ensure full target coverage, advanced dose calculation methods like Monte Carlo simulations may be necessary in proton therapy. Monte Carlo simulations may also be required to avoid biases resulting from systematic discrepancies in calculated dose distributions for clinical trials comparing proton therapy with conventional radiation therapy.

Assessment of radiation-induced second cancer risks in proton therapy and IMRT for organs inside the primary radiation field.

There is clinical evidence that second malignancies in radiation therapy occur mainly within the beam path, i.e. in the medium or high-dose region. The purpose of this study was to assess the risk for developing a radiation-induced tumor within the treated volume and to compare this risk for proton therapy and intensity-modulated photon therapy (IMRT). Instead of using data for specific patients we have created a representative scenario. Fully contoured age- and gender-specific whole body phantoms (4 year and 14 year old) were uploaded into a treatment planning system and tumor volumes were contoured based on patients treated for optic glioma and vertebral body Ewing's sarcoma. Treatment plans for IMRT and proton therapy treatments were generated. Lifetime attributable risks (LARs) for developing a second malignancy were calculated using a risk model considering cell kill, mutation, repopulation, as well as inhomogeneous organ doses. For standard fractionation schemes, the LAR for developing a second malignancy from radiation therapy alone was found to be up to 2.7% for a 4 year old optic glioma patient treated with IMRT considering a soft-tissue carcinoma risk model only. Sarcoma risks were found to be below 1% in all cases. For a 14 year old, risks were found to be about a factor of 2 lower. For Ewing's sarcoma cases the risks based on a sarcoma model were typically higher than the carcinoma risks, i.e. LAR up to 1.3% for soft-tissue sarcoma. In all cases, the risk from proton therapy turned out to be lower by at least a factor of 2 and up to a factor of 10. This is mainly due to lower total energy deposited in the patient when using proton beams. However, the comparison of a three-field and four-field proton plan also shows that the distribution of the dose, i.e. the particular treatment plan, plays a role. When using different fractionation schemes, the estimated risks roughly scale with the total dose difference in%. In conclusion, proton therapy can significantly reduce the risk for developing an in-field second malignancy. The risk depends on treatment planning parameters, i.e. an analysis based on our formalism could be applied within treatment planning programs to guide treatment plans for pediatric patients.

Range uncertainty in proton therapy due to variable biological effectiveness.

Traditionally, dose in proton radiotherapy is prescribed as Gy(RBE) by scaling up the physical dose by 10%. The relative biological effectiveness (RBE) of protons is considered to vary with dose-averaged linear energy transfer (LET(d)), dose (d) and (α/ß)(x). The increase of RBE with depth causes a shift of the falloff of the beam, i.e. a change of the beam range. The magnitude of this shift will depend on dose and (α/ß)(x). The aim of this project was to quantify the dependence of the range shift on these parameters. Three double-scattered beams of different ranges incident on a computational phantom consisting of different regions of interest (ROIs) were used. Each ROI was assigned with (α/ß)(x) values between 0.5 and 20 Gy. The distribution of LET(d) within each ROI was obtained from a Monte Carlo simulation. The LET(d) distribution depends on the beam energy and thus its nominal range. The RBE values within the ROIs were calculated for doses between 1 and 15 Gy using an in-house developed biophysical model. Dose-volume histograms of the RBE-weighted doses were extracted for each ROI for a 'fixed RBE' (RBE = 1.1) and a 'variable RBE' (RBE = f (d, α/ß, LET(d))), and the percentage difference in range was obtained from the difference of the percentage volumes at the distal 80% of the dose. Range differences in normal tissue ((α/ß)(x) = 3 Gy) of the order of 3-2 mm were obtained, respectively, for a shallow (physical range 4.8 cm) and a deep (physical range 12.8 cm) beam, when a dose of 1 Gy normalized to the mid-SOBP was delivered. As the dose increased to 15 Gy, the variable RBE decreases below 1.1 which induces ranges of about 1 mm shorter than those obtained with an RBE of 1.1. The shift in the range of an SOBP when comparing biological dose distributions obtained with a fixed or a variable RBE was quantified as a function of dose, (α/ß)(x) and physical range (as a surrogate of the initial beam energy). The shift increases with the physical range but decreases with increasing dose or (α/ß)(x). The results of our study allow a quantitative consideration of RBE-caused range uncertainties as a function of treatment site and dose in treatment planning.

Comparison of whole-body phantom designs to estimate organ equivalent neutron doses for secondary cancer risk assessment in proton therapy.

Secondary neutron fluence created during proton therapy can be a significant source of radiation exposure in organs distant from the treatment site, especially in pediatric patients. Various published studies have used computational phantoms to estimate neutron equivalent doses in proton therapy. In these simulations, whole-body patient representations were applied considering either generic whole-body phantoms or generic age- and gender-dependent phantoms. No studies to date have reported using patient-specific geometry information. The purpose of this study was to estimate the effects of patient­phantom matching when using computational pediatric phantoms. To achieve this goal, three sets of phantoms, including different ages and genders, were compared to the patients' whole-body CT. These sets consisted of pediatric age specific reference, age-adjusted reference and anatomically sculpted phantoms. The neutron equivalent dose for a subset of out-of-field organs was calculated using the GEANT4 Monte Carlo toolkit, where proton fields were used to irradiate the cranium and the spine of all phantoms and the CT-segmented patient models. The maximum neutron equivalent dose per treatment absorbed dose was calculated and found to be on the order of 0 to 5 mSv Gy(-1). The relative dose difference between each phantom and their respective CT-segmented patient model for most organs showed a dependence on how close the phantom and patient heights were matched. The weight matching was found to have much smaller impact on the dose accuracy except for very heavy patients. Analysis of relative dose difference with respect to height difference suggested that phantom sculpting has a positive effect in terms of dose accuracy as long as the patient is close to the 50th percentile height and weight. Otherwise, the benefit of sculpting was masked by inherent uncertainties, i.e. variations in organ shapes, sizes and locations.Other sources of uncertainty included errors associated with beam positioning, neutron weighting factor definition and organ segmentation. This work demonstrated the importance of hybrid phantom height matching for more accurate organ dose calculation in proton therapy and the potential limitations of reference phantoms released by regulatory bodies for radiation therapy applications.