Renormalization of radiobiological response functions by energy loss fluctuations and complexities in chromosome aberration induction: deactivation theory for proton therapy from cells to tumor control

We employ a multi-scale mechanistic approach to investigate radiation induced cell toxicities and deactivation mechanisms as a function of linear energy transfer in hadron therapy. Our theoretical model consists of a system of Markov chains in microscopic and macroscopic spatio-temporal landscapes, i.e., stochastic birth-death processes of cells in millimeter-scale colonies that incorporates a coarse-grained driving force to account for microscopic radiation induced damage. The coupling, hence the driving force in this process, stems from a nano-meter scale radiation induced DNA damage that incorporates the enzymatic end-joining repair and mis-repair mechanisms. We use this model for global fitting of the high-throughput and high accuracy clonogenic cell-survival data acquired under exposure of the therapeutic scanned proton beams, the experimental design that considers $\gamma$-H2AX as the biological endpoint and exhibits maximum observed achievable dose and LET, beyond which the majority of the cells undergo collective biological deactivation processes. An estimate to optimal dose and LET calculated from tumor control probability by extension to $~ 10^6$ cells per $mm$-size voxels is presented. We attribute the increase in degree of complexity in chromosome aberration to variabilities in the observed biological responses as the beam linear energy transfer (LET) increases, and verify consistency of the predicted cell death probability with the in-vitro cell survival assay of approximately 100 non-small cell lung cancer (NSCLC) cells

Is a 3-mm intrafractional margin sufficient for daily image-guided intensity-modulated radiation therapy of prostate cancer?

PURPOSE: To determine whether a 3-mm isotropic target margin adequately covers the prostate and seminal vesicles (SVs) during administration of an intensity-modulated radiation therapy (IMRT) treatment fraction, assuming that daily image-guided setup is performed just before each fraction. MATERIALS AND METHODS: In-room computed tomographic (CT) scans were acquired immediately before and after a daily treatment fraction in 46 patients with prostate cancer. An eight-field IMRT plan was designed using the pre-fraction CT with a 3-mm margin and subsequently recalculated on the post-fraction CT. For convenience of comparison, dose plans were scaled to full course of treatment (75.6 Gy). Dose coverage was assessed on the post-treatment CT image set. RESULTS: During one treatment fraction (21.4+/-5.5 min), there were reductions in the volumes of the prostate and SVs receiving the prescribed dose (median reduction 0.1% and 1.0%, respectively, p\u3c0.001) and in the minimum dose to 0.1 cm(3) of their volumes (median reduction 0.5 and 1.5 Gy, p\u3c0.001). Of the 46 patients, three patients\u27 prostates and eight patients\u27 SVs did not maintain dose coverage above 70 Gy. Rectal filling correlated with decreased percentage-volume of SV receiving 75.6, 70, and 60 Gy (p\u3c0.02). CONCLUSIONS: The 3-mm intrafractional margin was adequate for prostate dose coverage. However, a significant subset of patients lost SV dose coverage. The rectal volume change significantly affected SV dose coverage. For advanced-stage prostate cancers, we recommend to use larger margins or improve organ immobilization (such as with a rectal balloon) to ensure SV coverage

Establishing the feasibility of the dosimetric compliance criteria of RTOG 1308: phase III randomized trial comparing overall survival after photon versus proton radiochemotherapy for inoperable stage II-IIIB NSCLC.

BACKGROUND: To establish the feasibility of the dosimetric compliance criteria of the RTOG 1308 trial through testing against Intensity Modulation Radiation Therapy (IMRT) and Passive Scattering Proton Therapy (PSPT) plans. METHODS: Twenty-six lung IMRT and 26 proton PSPT plans were included in the study. Dose Volume Histograms (DVHs) for targets and normal structures were analyzed. The quality of IMRT plans was assessed using a knowledge-based engineering tool. RESULTS: Most of the RTOG 1308 dosimetric criteria were achieved. The deviation unacceptable rates were less than 10 % for most criteria; however, a deviation unacceptable rate of more than 20 % was computed for the planning target volume minimum dose compliance criterion. Dose parameters for the target volume were very close for the IMRT and PSPT plans. However, the PSPT plans led to lower dose values for normal structures. The dose parameters in which PSPT plans resulted in lower values than IMRT plans were: lung V5Gy (%) (34.4 in PSPT and 47.2 in IMRT); maximum spinal cord dose (31.7 Gy in PSPT and 43.5 Gy in IMRT); heart V5Gy (%) (19 in PSPT and 47 in IMRT); heart V30Gy (%) (11 in PSPT and 19 in IMRT); heart V45Gy (%) (7.8 in PSPT and 12.1 in IMRT); heart V50% (Gy) (7.1 in PSPT and 9.8 in IMRT) and mean heart dose (7.7 Gy in PSPT and 14.9 Gy in IMRT). CONCLUSIONS: The revised RTOG 1308 dosimetric compliance criteria are feasible and achievable

Incorporating Variable RBE in IMPT Optimization for Ependymoma

PURPOSE: To study the dosimetric impact of incorporating variable relative biological effectiveness (RBE) of protons in optimizing intensity-modulated proton therapy (IMPT) treatment plans and to compare it with conventional constant RBE optimization and linear energy transfer (LET)-based optimization. METHODS: This study included 10 pediatric ependymoma patients with challenging anatomical features for treatment planning. Four plans were generated for each patient according to different optimization strategies: (1) constant RBE optimization (ConstRBEopt) considering standard-of-care dose requirements; (2) LET optimization (LETopt) using a composite cost function simultaneously optimizing dose-averaged LET (LET RESULTS: We found that the LETopt plans consistently achieved increased LET in tumor targets and similar or decreased LET in critical organs compared to other plans. On average, the VarRBEopt plans achieved lower mean and maximum doses with both constant and variable RBE in the brainstem and spinal cord for all 10 patients. To compensate for the underdosing of targets with 1.1 RBE for the VarRBEopt plans, the hRBEopt plans achieved higher physical dose in targets and reduced mean and especially maximum variable RBE doses compared to the ConstRBEopt and LETopt plans. CONCLUSION: We demonstrated the feasibility of directly incorporating variable RBE models in IMPT optimization. A hybrid RBE optimization strategy showed potential for clinical implementation by maintaining all current dose limits and reducing the incidence of high RBE in critical normal tissues in ependymoma patients

Can megavoltage computed tomography reduce proton range uncertainties in treatment plans for patients with large metal implants?

Treatment planning calculations for proton therapy require an accurate knowledge of radiological path length, or range, to the distal edge of the target volume. In most cases, the range may be calculated with sufficient accuracy using kilovoltage (kV) computed tomography (CT) images. However, metal implants such as hip prostheses can cause severe streak artifacts that lead to large uncertainties in proton range. The purposes of this study were to quantify streak-related range errors and to determine if they could be avoided by using artifact-free megavoltage (MV) CT images in treatment planning. Proton treatment plans were prepared for a rigid, heterogeneous phantom and for a prostate cancer patient with a metal hip prosthesis using corrected and uncorrected kVCT images alone, uncorrected MVCT images and a combination of registered MVCT and kVCT images (the hybrid approach). Streak-induced range errors of 5-12 mm were present in the uncorrected kVCT-based patient plan. Correcting the streaks by manually assigning estimated true Hounsfield units improved the range accuracy. In a rigid heterogeneous phantom, the implant-related range uncertainty was estimated at approach, the kVCT images provided good delineation of soft tissues due to high-contrast resolution, and the streak-free MVCT images provided smaller range uncertainties because they did not require artifact correction. © 2008 Institute of Physics and Engineering in Medicine

Algorithm and performance of a clinical IMRT beam-angle optimization system

This paper describes the algorithm and examines the performance of an IMRT beam-angle optimization (BAO) system. In this algorithm successive sets of beam angles are selected from a set of predefined directions using a fast simulated annealing (FSA) algorithm. An IMRT beam-profile optimization is performed on each generated set of beams. The IMRT optimization is accelerated by using a fast dose calculation method that utilizes a precomputed dose kernel. A compact kernel is constructed for each of the predefined beams prior to starting the FSA algorithm. The IMRT optimizations during the BAO are then performed using these kernels in a fast dose calculation engine. This technique allows the IMRT optimization to be performed more than two orders of magnitude faster than a similar optimization that uses a convolution dose calculation engine.Comment: Final version that appeared in Phys. Med. Biol. 48 (2003) 3191-3212. Original EPS figures have been converted to PNG files due to size limi