Linear energy transfer-guided optimization in intensity modulated proton therapy: feasibility study and clinical potential.

PURPOSE: To investigate the feasibility and potential clinical benefit of linear energy transfer (LET) guided plan optimization in intensity modulated proton therapy (IMPT). METHODS AND MATERIALS: A multicriteria optimization (MCO) module was used to generate a series of Pareto-optimal IMPT base plans (BPs), corresponding to defined objectives, for 5 patients with head-and-neck cancer and 2 with pancreatic cancer. A Monte Carlo platform was used to calculate dose and LET distributions for each BP. A custom-designed MCO navigation module allowed the user to interpolate between BPs to produce deliverable Pareto-optimal solutions. Differences among the BPs were evaluated for each patient, based on dose-volume and LET-volume histograms and 3-dimensional distributions. An LET-based relative biological effectiveness (RBE) model was used to evaluate the potential clinical benefit when navigating the space of Pareto-optimal BPs. RESULTS: The mean LET values for the target varied up to 30% among the BPs for the head-and-neck patients and up to 14% for the pancreatic cancer patients. Variations were more prominent in organs at risk (OARs), where mean LET values differed by a factor of up to 2 among the BPs for the same patient. An inverse relation between dose and LET distributions for the OARs was typically observed. Accounting for LET-dependent variable RBE values, a potential improvement on RBE-weighted dose of up to 40%, averaged over several structures under study, was noticed during MCO navigation. CONCLUSIONS: We present a novel strategy for optimizing proton therapy to maximize dose-averaged LET in tumor targets while simultaneously minimizing dose-averaged LET in normal tissue structures. MCO BPs show substantial LET variations, leading to potentially significant differences in RBE-weighted doses. Pareto-surface navigation, using both dose and LET distributions for guidance, provides the means for evaluating a large variety of deliverable plans and aids in identifying the clinically optimal solution.

Variations in linear energy transfer within clinical proton therapy fields and the potential for biological treatment planning.

PURPOSE: To calculate the linear energy transfer (LET) distributions in patients undergoing proton therapy. These distributions can be used to identify areas of elevated or diminished biological effect. The location of such areas might be influenced in intensity-modulated proton therapy (IMPT) optimization. METHODS AND MATERIALS: Because Monte Carlo studies to investigate the LET distribution in patients have not been undertaken so far, the code is first validated with simulations in water. The code was used in five patients, for each of them three planning and delivery techniques were simulated: passive scattering, three-dimensional modulation IMPT (3D-IMPT), and distal edge tracking IMPT (DET-IMPT). RESULTS: The inclusion of secondary particles led to significant differences compared with analytical techniques. In addition, passive scattering and 3D-IMPT led to largely comparable LET distributions, whereas the DET-IMPT plans resulted in considerably increased LET values in normal tissues and critical structures. In the brainstem, dose-averaged LET values exceeding 5 keV/µm were observed in areas with significant dose (>70% of prescribed dose). In noncritical normal tissues, even values >8 keV/µm occurred. CONCLUSION: This work demonstrates that active scanning offers the possibility of influencing the distribution of dose-averaged LET (i.e., the biological effect) without significantly altering the distribution of physical dose. On the basis of this finding, we propose a method to alter deliberately the LET distribution of a treatment plan in such a manner that the LET is maximized within certain target areas and minimized in normal tissues, while maintaining the prescribed target dose and dose constraints for organs at risk.

Monte Carlo calculation of imaging doses from diagnostic multidetector CT and kilovoltage cone-beam CT as part of prostate cancer treatment plans.

PURPOSE: To calculate imaging doses to the rectum, bladder, and femoral heads as part of a prostate cancer treatment plans, assuming an image guided radiation therapy (IGRT) procedure involving either the multidetector CT (MDCT) or kilovoltage cone-beam CT (kV CBCT). METHODS: This study considered an IGRT treatment plan for a prostate carcinoma patient involving 50.4 Gy from 28 initial fractions and a boost of 28.8 Gy from 16 fractions. A total of 45 CT imaging procedures, each involving a MDCT or a kV CBCT scan procedure, were carefully modeled using the MCNPX code version 2.5.0. The MDCT scanner model is based on the GE LightSpeed 16-MDCT scanner and the kV CBCT scanner model is based on the Varian On-Board Imager using parameters reported by the CT manufacturers and literatures. A patient-specific treatment planning CT data set was used to construct the phantom for the dose calculation. The target, organs-at-risk (OARs), and background voxels in the CT data set were categorized into six tissue types according to CT numbers for Monte Carlo calculations. RESULTS: For a total of 45 imaging procedures, it was found that the rectum received 78.4 and 76.7 cGy from MDCT and kV CBCT, respectively. The bladder received slightly greater doses of 82.4 and 77.9 cGy, while the femoral heads received much higher doses of 182.3 and 141.3 cGy from MDCT and kV CBCT, respectively. To investigate the impact of these imaging doses on treatment planning, OAR doses from MDCT or kV CBCT imaging procedures were added to the corresponding dose matrix reported by the original treatment plans to construct dose volume histograms. It was found that after the imaging dose is added, the rectum volumes irradiated to 75 and 70 Gy increased from 13.9% and 21.2%, respectively, in the original plan to 14.8% and 21.8%. The bladder volumes receiving 80 Gy increased to 4.6% from 4.1% in the original plan and the volume receiving 75 Gy increased to 7.9% from 7.5%. All values remained within the tolerance levels: V70<25%, V75 <15% for rectum and V75 < 25%, V80 < 15% for bladder. The irradiation of femoral heads was also acceptable with no volume receiving >45 Gy. CONCLUSIONS: IGRT procedures can irradiate the OARs to an imaging dose level that is great enough to require careful evaluation and perhaps even adjustment of original treatment planning in order to still satisfy the dose constraints. This study only considered one patient CT because the CT x rays cover a relatively larger volume of the body and the dose distribution is considerably more uniform than those associated with the therapeutic beams. As a result, the dose to an organ from CT imaging doses does not vary much from one patient to the other for the same CT settings. One factor that would potentially affect such CT dose level is the size of the patient body. More studies are needed to develop accurate and convenient methods of accounting for the imaging doses as part of treatment planning.

Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No.

PURPOSE: Evaluate the rationale for the proposals that prior to a wider use of proton radiation therapy there must be supporting data from phase III clinical trials. That is, would less dose to normal tissues be an advantage to the patient? METHODS: Assess the basis for the assertion that proton dose distributions are superior to those of photons for most situations. Consider the requirements for determining the risks of normal tissue injury, acute and remote, in the examination of the data from a trial. Analyze the probable cost differential between high technology photon and proton therapy. Evaluate the rationale for phase III clinical trials of proton vs photon radiation therapy when the only difference in dose delivered is a difference in distribution of low LET radiation. RESULTS: The distributions of biological effective dose by protons are superior to those by X-rays for most clinical situations, viz. for a defined dose and dose distribution to the target by protons there is a lower dose to non-target tissues. This superiority is due to these physical properties of protons: (1) protons have a finite range and that range is exclusively dependent on the initial energy and the density distribution along the beam path; (2) the Bragg peak; (3) the proton energy distribution may be designed to provide a spread out Bragg peak that yields a uniform dose across the target volume and virtually zero dose deep to the target. Importantly, proton and photon treatment plans can employ beams in the same number and directions (coplanar, non-co-planar), utilize intensity modulation and employ 4D image guided techniques. Thus, the only difference between protons and photons is the distribution of biologically effective dose and this difference can be readily evaluated and quantified. Additionally, this dose distribution advantage should increase the tolerance of certain chemotherapeutic agents and thus permit higher drug doses. The cost of service (not developmental) proton therapy performed in 3-5 gantry centers operating 14-16 h/day and 6 days/week is likely to be equal to or less than twice that of high technology X-ray therapy. CONCLUSIONS: Proton therapy provides superior distributions of low LET radiation dose relative to that by photon therapy for treatment of a large proportion of tumor/normal tissue situations. Our assessment is that there is no medical rationale for clinical trials of protons as they deliver lower biologically effective doses to non-target tissue than do photons for a specified dose and dose distribution to the target. Based on present knowledge, there will be some gain for patients treated by proton beam techniques. This is so even though quantitation of the clinical gain is less secure than the quantitation of reduction in physical dose. Were proton therapy less expensive than X-ray therapy, there would be no interest in conducting phase III trails. The talent, effort and funds required to conduct phase III clinical trials of protons vs photons would surely be more productive in the advancement of radiation oncology if employed to investigate real problems, e.g. the most effective total dose, dose fractionation, definition of CTV and GTV, means for reduction of PTV and the gains and risks of combined modality therapy.

Temporo-spatial IMRT optimization: concepts, implementation and initial results.

With the recent availability of 4D-CT, the accuracy of information on internal organ motion during respiration has improved significantly. We investigate the utility of organ motion information in IMRT treatment planning, using an in-house prototype optimization system. Four approaches are compared: (1) planning with optimized margins, based on motion information; (2) the 'motion kernel' approach, in which a more accurate description of the dose deposit from a pencil beam to a moving target is achieved either through time-weighted averaging of influence matrices, calculated for different instances of anatomy (subsets of 4D-CT data, corresponding to various phases of motion) or through convolution of the pencil beam kernel with the probability density function describing the target motion; (3) optimal gating, or tracking with beam intensity maps optimized independently for each instance of anatomy; and (4) optimal tracking with beam intensity maps optimized simultaneously for all instances of anatomy. The optimization is based on a gradient technique and can handle both physical (dose-volume) and equivalent uniform dose constraints. Optimization requires voxel mapping from phase to phase in order to score the dose in individual voxels as they move. The results show that, compared to the other approaches, margin expansion has a significant disadvantage by substantially increasing the integral dose to patient. While gating or tracking result in the best dose conformation to the target, the former elongates treatment time, and the latter significantly complicates the delivery procedure. The 'motion kernel' approach does not provide a dosimetric advantage, compared to optimal tracking or gating, but might lead to more efficient delivery. A combination of gating with the 'motion kernel' or margin expansion approach will increase the duty cycle and may provide one with the most efficient solution, in terms of complexity of the delivery procedure and dose conformality to the target.

Proton beams to replace photon beams in radical dose treatments.

With proton beam radiation therapy a smaller volume of normal tissues is irradiated at high dose levels for most anatomic sites than is feasible with any photon technique. This is due to the Laws of Physics, which determine the absorption of energy from photons and protons. In other words, the dose from a photon beam decreases exponentially with depth in the irradiated material. In contrast, protons have a finite range and that range is energy dependent. Accordingly, by appropriate distribution of proton energies, the dose can be uniform across the target and essentially zero deep to the target and the atomic composition of the irradiated material. The dose proximal to the target is lower compared with that in photon techniques, for all except superficial targets This resultant closer approximation of the planning treatment volume (PTV) to the CTV/GTV (grossly evident tumor volume/subclinical tumor extensions) constitutes a clinical gain by definition; i.e. a smaller treatment volume that covers the target three dimensionally for the entirety of each treatment session provides a clinical advantage. Several illustrative clinical dose distributions are presented and the clinical outcome results are reviewed briefly. An important technical advance will be the use of intensity modulated proton radiation therapy, which achieves contouring of the proximal edge of the SOBP (spread out Bragg peak) as well as the distal edge. This technique uses pencil beam scanning. To permit further progressive reductions of the PTV, 4-D treatment planning and delivery is required. The fourth dimension is time, as the position and contours of the tumor and the adjacent critical normal tissues are not constant. A potentially valuable new method for assessing the clinical merits of each of a large number of treatment plans is the evaluation of multidimensional plots of the complication probabilities for each of 'n' critical normal tissues/ structures for a specified tumor control probability. The cost of proton therapy compared with that of very high technology photon therapy is estimated and evaluated. The differential is estimated to be approximately 1.5 provided there were to be no charge for the original facility and that there were sufficient patients for operating on an extended schedule (6-7 days of 14-16 h) with > or = two gantries and one fixed horizontal beam.