Proton Therapy For Lung Cancer Research Articles

Potential for Improvements in Robustness and Optimality of Intensity-Modulated Proton Therapy for Lung Cancer with 4-Dimensional Robust Optimization.

Background: Major challenges in the application of intensity-modulated proton therapy (IMPT) for lung cancer patients include the uncertainties associated with breathing motion, its mitigation and its consideration in IMPT optimization. The primary objective of this research was to evaluate the potential of four-dimensional robust optimization (4DRO) methodology to make IMPT dose distributions resilient to respiratory motion as well as to setup and range uncertainties; Methods: The effect of respiratory motion, characterized by different phases of 4D computed tomography (4DCT), was incorporated into an in-house 4DRO system. Dose distributions from multiple setup and range uncertainty scenarios were calculated for each of the ten phases of CT datasets. The 4DRO algorithm optimizes dose distributions to achieve target dose coverage and normal tissue sparing for multiple setup and range uncertainty scenarios as well as for all ten respiratory phases simultaneously. IMPT dose distributions of ten lung cancer patients with different tumor sizes and motion magnitudes were optimized to illustrate our approach and its potential; Results: Compared with treatment plans generated using the conventional planning target volume (PTV)-based optimization and 3D robust optimization (3DRO), plans generated by 4DRO were found to have superior clinical target volume coverage and dose robustness in the face of setup and range uncertainties as well as for respiratory motion. In most of the cases we studied, 4DRO also resulted in more homogeneous target dose distributions. Interestingly, such improvements were found even for cases in which moving diaphragms intruded into the proton beam paths; Conclusion: The incorporation of respiratory motion, along with setup and range uncertainties, into robust optimization, has the potential to improve the resilience of target and normal tissue dose distributions in IMPT plans in the face of the uncertainties considered. Moreover, it improves the optimality of plans compared to PTV-based optimization as well as 3DRO.

Robustness and Organ Sparing Potential of Intensity Modulated Proton Therapy for Lung Cancer

Robustness and Organ Sparing Potential of Intensity Modulated Proton Therapy for Lung Cancer

EP-1912: Robustness and organ sparing potential of intensity modulated proton therapy for lung cancer

EP-1912: Robustness and organ sparing potential of intensity modulated proton therapy for lung cancer

Image guidance in proton therapy for lung cancer.

Proton therapy is a promising but challenging treatment modality for the management of lung cancer. The technical challenges are due to respiratory motion, low dose tolerance of adjacent normal tissue and tissue density heterogeneity. Different imaging modalities are applied at various steps of lung proton therapy to provide information on target definition, target motion, proton range, patient setup and treatment outcome assessment. Imaging data is used to guide treatment design, treatment delivery, and treatment adaptation to ensure the treatment goal is achieved. This review article will summarize and compare various imaging techniques that can be used in every step of lung proton therapy to address these challenges.

PO-0946: Breath-hold motion effect in pencil beam scanned proton therapy for lung cancer – experimental study

PO-0946: Breath-hold motion effect in pencil beam scanned proton therapy for lung cancer – experimental study

Advances in proton therapy in lung cancer.

Lung cancer remains the leading cause of cancer deaths in the United States (US) and worldwide. Radiation therapy is a mainstay in the treatment of locally advanced non-small cell lung cancer (NSCLC) and serves as an excellent alternative for early stage patients who are medically inoperable or who decline surgery. Proton therapy has been shown to offer a significant dosimetric advantage in NSCLC patients over photon therapy, with a decrease in dose to vital organs at risk (OARs) including the heart, lungs and esophagus. This in turn, can lead to a decrease in acute and late toxicities in a population already predisposed to lung and cardiac injury. Here, we present a review on proton treatment techniques, studies, clinical outcomes and toxicities associated with treating both early stage and locally advanced NSCLC.

Proton therapy for lung cancer: Current uses and future applications for early stage and locally advanced non-small cell lung cancer

Proton therapy for lung cancer: Current uses and future applications for early stage and locally advanced non-small cell lung cancer

SU‐F‐T‐133: Uniform Scanning Proton Therapy for Lung Cancer: Toxicity and Its Correlation with Dosimetry

Purpose:To analyze the toxicity of uniform scanning proton therapy for lung cancer patients and its correlation with dose distribution.Methods:In this study, we analyzed the toxicity of 128 lung cancer patients, including 18 small cell lung cancer and 110 non small cell lung cancer patients. Each patient was treated with uniform scanning proton beams at our center using typically 2–4 fields. The prescription was typically 74 Cobalt gray equivalent (CGE) at 2 CGE per fraction. 4D Computerized Tomography (CT) scans were used to evaluate the target motion and contour the internal target volume, and repeated 3 times during the course of treatment to evaluate the need for plan adaptation. Toxicity data for these patients were obtained from the proton collaborative group (PCG) database. For cases of grade 3 toxicities or toxicities of interest such as esophagitis and radiation dermatitis, dose distributions were reviewed and analyzed in attempt to correlate the toxicity with radiation dose.Results:At a median follow up time of about 21 months, none of the patients had experienced Grade 4 or 5 toxicity. The most common adverse effect was dermatitis (81%: 52%‐Grade 1, 28%‐Grade 2, and 1% Grade 3), followed by fatigue (48%), Cough (46%), and Esophagitis (45%), as shown in Figure 1. Severe toxicities, such as Grade 3 dermatitis or pain of skin, had a clear correlation with high radiation dose.Conclusion:Uniform scanning proton therapy is well tolerated by lung cancer patients. Preliminary analysis indicates there is correlation between severe toxicity and high radiation dose. Understanding of radiation resulted toxicities and careful choice of beam arrangement are critical in minimizing toxicity of skin and other organs.

SU‐F‐T‐134: Can We Use the Same Dose Constrains Learnt From Photon World to Plan Proton for Lung Cancer?

Purpose:To evaluate if the same DVH constrains used in photon plans can be safely used to plan proton therapy for lung cancer. Since protons and photons have different dose deposition patterns, the hypothesis is following DVH constrains derived from photon world is not safe for proton.Methods:We retrospectively evaluated plans for 11 lung cancer patients. Each patient was planned with photon and proton following the same dose constrains. Dose statistics on PTV, normal lung, heart and esophagus were extracted for comparison. gEUD for normal lung was calculated and compared between proton and photon plans. We calculated series of gEUDs for each plan by varying the parameter “a” in gEUD formula from 0.1 to 3, covering the whole confidence interval.Results:For all patients, proton plans yield similar PTV coverage and lower dose to heart and esophagus than photon plans. Normal lung V5 was 32.3 % on average in proton plans than 55.4 % in photon. Normal lung gEUD monotonically increased with increasing “a” for all proton and photon plans. For a given patient, the gEUD_proton(a) had a steeper slope than gEUD_photon(a). The two curves crossed for 8 out of 11 patients when “a” = [0.1, 3]. a_crossing ranged from 0.8 to 2.44 with an average of 1.15. For a<a_crossing, gEUD_proton was less than gEUD_photon and vice versa.Conclusion:The current clinical guideline is the lower normal lung V5 would associated with less complications. However, proton plans with a lower normal lung V5 could yield a higher gEUD than photon if the real “a” is larger than a_crossing. Since a_crossing was within the possible range of real “a”, simply following the normal lung V5 guideline for proton plan would not be a good practice. More comprehensive methods should be developed to evaluate the proton plan.

First Clinical Investigation of Cone Beam Computed Tomography and Deformable Registration for Adaptive Proton Therapy for Lung Cancer

An adaptive proton therapy workflow using cone beam computed tomography (CBCT) is proposed. It consists of an online evaluation of a fast range-corrected dose distribution based on a virtual CT (vCT) scan. This can be followed by more accurate offline dose recalculation on the vCT scan, which can trigger a rescan CT (rCT) for replanning. The workflow was tested retrospectively for 20 consecutive lung cancer patients. A diffeomorphic Morphon algorithm was used to generate the lung vCT by deforming the average planning CT onto the CBCT scan. An additional correction step was applied to account for anatomic modifications that cannot be modeled by deformation alone. A set of clinical indicators for replanning were generated according to the water equivalent thickness (WET) and dose statistics and compared with those obtained on the rCT scan. The fast dose approximation consisted of warping the initial planned dose onto the vCT scan according to the changes in WET. The potential under- and over-ranges were assessed as a variation in WET at the target's distal surface. The range-corrected dose from the vCT scan reproduced clinical indicators similar to those of the rCT scan. The workflow performed well under different clinical scenarios, including atelectasis, lung reinflation, and different types of tumor response. Between the vCT and rCT scans, we found a difference in the measured 95% percentile of the over-range distribution of 3.4 ± 2.7 mm. The limitations of the technique consisted of inherent uncertainties in deformable registration and the drawbacks of CBCT imaging. The correction step was adequate when gross errors occurred but could not recover subtle anatomic or density changes in tumors with complex topology. A proton therapy workflow based on CBCT provided clinical indicators similar to those using rCT for patients with lung cancer with considerable anatomic changes.

Exploratory Study of 4D versus 3D Robust Optimization in Intensity Modulated Proton Therapy for Lung Cancer

The purpose of this study was to compare the impact of uncertainties and interplay on 3-dimensional (3D) and 4D robustly optimized intensity modulated proton therapy (IMPT) plans for lung cancer in an exploratory methodology study. IMPT plans were created for 11 nonrandomly selected non-small cell lung cancer (NSCLC) cases: 3D robustly optimized plans on average CTs with internal gross tumor volume density overridden to irradiate internal target volume, and 4D robustly optimized plans on 4D computed tomography (CT) to irradiate clinical target volume (CTV). Regular fractionation (66 Gy [relative biological effectiveness; RBE] in 33 fractions) was considered. In 4D optimization, the CTV of individual phases received nonuniform doses to achieve a uniform cumulative dose. The root-mean-square dose-volume histograms (RVH) measured the sensitivity of the dose to uncertainties, and the areas under the RVH curve (AUCs) were used to evaluate plan robustness. Dose evaluation software modeled time-dependent spot delivery to incorporate interplay effect with randomized starting phases of each field per fraction. Dose-volume histogram (DVH) indices comparing CTV coverage, homogeneity, and normal tissue sparing were evaluated using Wilcoxon signed rank test. 4D robust optimization plans led to smaller AUC for CTV (14.26 vs 18.61, respectively; P=.001), better CTV coverage (Gy [RBE]) (D95% CTV: 60.6 vs 55.2, respectively; P=.001), and better CTV homogeneity (D5%-D95% CTV: 10.3 vs 17.7, respectively; P=.002) in the face of uncertainties. With interplay effect considered, 4D robust optimization produced plans with better target coverage (D95% CTV: 64.5 vs 63.8, respectively; P=.0068), comparable target homogeneity, and comparable normal tissue protection. The benefits from 4D robust optimization were most obvious for the 2 typical stage III lung cancer patients. Our exploratory methodology study showed that, compared to 3D robust optimization, 4D robust optimization produced significantly more robust and interplay-effect-resistant plans for targets with comparable dose distributions for normal tissues. A further study with a larger and more realistic patient population is warranted to generalize the conclusions.

A Novel 4-D Robust Optimization Mitigates Interplay Effect in Intensity Modulated Proton Therapy for Lung Cancer

A Novel 4-D Robust Optimization Mitigates Interplay Effect in Intensity Modulated Proton Therapy for Lung Cancer

SU‐E‐J‐247: Time Evolution of Radiation‐Induced Lung Injury After Stereotactic Proton Therapy

Purpose:Quantitative metrics to assess patient‐specific radiation‐induced lung injury have the potential to guide individualization of therapy and be early indicators of recurrence. Here we investigate computed tomography (CT) density changes in normal lung after stereotactic Proton Therapy.Methods:Participants in a phase‐I clinical trial for stereotactic body radiation therapy (SBRT) with protons are analyzed on a rolling basis. The dataset includes 9 patients with 34 CT images to date. Follow‐up images are registered to the planning CT using deformable image registration and the change in CT density is correlated to the dose to examine the time‐evolution of Hounsfield Unit (HU) changes after large doses of proton radiation.Results:The lung density observed on the follow‐up images increases significantly with dose for all dose levels above 5 Gy(RBE) (p<0.001) for 8/9 patients. The change per unit dose [HU/Gy] varies significantly among the patients, from 0.1 (for the one patient without significant correlation) to 5.7 ΔHU/Gy(RBE). The current population average of ΔHU/Gy(RBE) is 2.1, i.e. a 1 Gy(RBE) increase in dose leads on average to a 2.1 HU increase in CT density. The slope of the dose‐response curve is constant for all timepoints investigated (from 3–24+ months). Additionally a pronounced non‐linearity in the dose response curve is noted for long follow‐up times (>18 months).Conclusion:CT density changes have a robust correlation with proton dose, quantitatively similar to photon dose, and may allow estimation of a patient's intrinsic radiosensitivity after proton therapy. The stability of the correlation with time however diverges from what is known about CT response after photon irradiation. This could have important implications for clinical decision‐making during proton therapy for lung cancer, especially for scheduling of follow‐up CT/PET imaging and diagnosis of recurrence.

SU‐F‐BRD‐01: A Novel 4D Robust Optimization Mitigates Interplay Effect in Intensity‐Modulated Proton Therapy for Lung Cancer

Purpose:To compare the impact of interplay effect on 3D and 4D robustly optimized intensity‐modulated proton therapy (IMPT) plans to treat lung cancer.Methods:Two IMPT plans were created for 11 non‐small‐cell‐lung‐cancer cases with 6–14 mm spots. 3D robust optimization generated plans on average CTs with the internal gross tumor volume density overridden to deliver 66 CGyE in 33 fractions to the internal target volume (ITV). 4D robust optimization generated plans on 4D CTs with the delivery of prescribed dose to the clinical target volume (CTV). In 4D optimization, the CTV of individual 4D CT phases received non‐uniform doses to achieve a uniform cumulative dose. Dose evaluation software was developed to model time‐dependent spot delivery to incorporate interplay effect with randomized starting phases of each field per fraction. Patient anatomy voxels were mapped from phase to phase via deformable image registration to score doses. Indices from dose‐volume histograms were used to compare target coverage, dose homogeneity, and normal‐tissue sparing. DVH indices were compared using Wilcoxon test.Results:Given the presence of interplay effect, 4D robust optimization produced IMPT plans with better target coverage and homogeneity, but slightly worse normal tissue sparing compared to 3D robust optimization (unit: Gy) [D95% ITV: 63.5 vs 62.0 (p=0.014), D5% ‐ D95% ITV: 6.2 vs 7.3 (p=0.37), D1% spinal cord: 29.0 vs 29.5 (p=0.52), Dmean total lung: 14.8 vs 14.5 (p=0.12), D33% esophagus: 33.6 vs 33.1 (p=0.28)]. The improvement of target coverage (D95%,4D – D95%,3D) was related to the ratio RMA3/(TVx10−4), with RMA and TV being respiratory motion amplitude (RMA) and tumor volume (TV), respectively. Peak benefit was observed at ratios between 2 and 10. This corresponds to 125 – 625 cm3 TV with 0.5‐cm RMA.Conclusion:4D optimization produced more interplay‐effect‐resistant plans compared to 3D optimization. It is most effective when respiratory motion is modest compared to TV.NIH/NCI K25CA168984; Eagles Cancer Research Career Development; The Lawrence W. and Marilyn W. Matteson Fund for Cancer Research; Mayo ASU Seed Grant; The Kemper Marley Foundation

The use of proton therapy in the treatment of lung cancers.

Lung cancer is the leading cause of death from cancer in the United States and worldwide. Radiation therapy plays a prominent role in the treatment of patients with nonmetastatic disease. Radiation therapy alone can be curative for patients with stage I non-small cell lung cancer (NSCLC). Radiation therapy is also used as part of multimodality therapy to treat patients with locally advanced NSCLC. Current treatment delivery is often limited by radiation doses received by normal structures and treatment-related toxicities. Proton therapy for lung cancer can reduce the dose received by normal tissues, including the lungs, esophagus, and spinal cord, and may allow for reduced treatment toxicities. Proton therapy may also more safely allow for reirradiation and for radiation therapy to be combined with chemotherapy and surgery. This review discusses the rationales for and current uses of proton therapy to treat lung cancer, and it highlights key studies of proton therapy to treat early-stage and locally advanced NSCLC.

Evaluation of the systematic error in using 3D dose calculation in scanning beam proton therapy for lung cancer.

The objective of this study was to evaluate and understand the systematic error between the planned three‐dimensional (3D) dose and the delivered dose to patient in scanning beam proton therapy for lung tumors. Single‐field and multifield optimized scanning beam proton therapy plans were generated for ten patients with stage II‐III lung cancer with a mix of tumor motion and size. 3D doses in CT datasets for different respiratory phases and the time‐weighted average CT, as well as the four‐dimensional (4D) doses were computed for both plans. The 3D and 4D dose differences for the targets and different organs at risk were compared using dose‐volume histogram (DVH) and voxel‐based techniques, and correlated with the extent of tumor motion. The gross tumor volume (GTV) dose was maintained in all 3D and 4D doses, using the internal GTV override technique. The DVH and voxel‐based techniques are highly correlated. The mean dose error and the standard deviation of dose error for all target volumes were both less than 1.5% for all but one patient. However, the point dose difference between the 3D and 4D doses was up to 6% for the GTV and greater than 10% for the clinical and planning target volumes. Changes in the 4D and 3D doses were not correlated with tumor motion. The planning technique (single‐field or multifield optimized) did not affect the observed systematic error. In conclusion, the dose error in 3D dose calculation varies from patient to patient and does not correlate with lung tumor motion. Therefore, patient‐specific evaluation of the 4D dose is important for scanning beam proton therapy for lung tumors.PACS number: 87.55.D

Evaluation and mitigation of the interplay effects of intensity modulated proton therapy for lung cancer in a clinical setting

PurposeThe primary aim of this study was to evaluate the impact of the interplay effects of intensity modulated proton therapy (IMPT) plans for lung cancer in the clinical setting. The secondary aim was to explore the technique of isolayered rescanning to mitigate these interplay effects. Methods and materialsA single-fraction 4-dimensional (4D) dynamic dose without considering rescanning (1FX dynamic dose) was used as a metric to determine the magnitude of dosimetric degradation caused by 4D interplay effects. The 1FX dynamic dose was calculated by simulating the machine delivery processes of proton spot scanning on a moving patient, described by 4D computed tomography during IMPT delivery. The dose contributed from an individual spot was fully calculated on the respiratory phase that corresponded to the life span of that spot, and the final dose was accumulated to a reference computed tomography phase by use of deformable image registration. The 1FX dynamic dose was compared with the 4D composite dose. Seven patients with various tumor volumes and motions were selected for study. ResultsThe clinical target volume (CTV) prescription coverage for the 7 patients was 95.04%, 95.38%, 95.39%, 95.24%, 95.65%, 95.90%, and 95.53% when calculated with the 4D composite dose and 89.30%, 94.70%, 85.47%, 94.09%, 79.69%, 91.20%, and 94.19% when calculated with the 1FX dynamic dose. For these 7 patients, the CTV coverage calculated by use of a single-fraction dynamic dose was 95.52%, 95.32%, 96.36%, 95.28%, 94.32%, 95.53%, and 95.78%, with a maximum monitor unit limit value of 0.005. In other words, by increasing the number of delivered spots in each fraction, the degradation of CTV coverage improved up to 14.6%. ConclusionsA single-fraction 4D dynamic dose without rescanning was validated as a surrogate to evaluate the interplay effects of IMPT for lung cancer in the clinical setting. The interplay effects potentially can be mitigated by increasing the amount of isolayered rescanning in each fraction delivery.

A method for selection of beam angles robust to intra-fractional motion in proton therapy of lung cancer

Background. Proton therapy offers the potential for sparing the normal tissue surrounding the target. However, due to well-defined proton ranges around the Bragg peak, dose deposition is more sensitive to changes in the water equivalent path length (WEPL) than with photons. In this study, we assess WEPL variations caused by breathing-induced motion for all possible beam angles in a series of lung cancer patients. By studying the association between measures for WEPL variation and breathing-induced target dose degradation we aimed to develop and explore a tool to identify beam angles that are robust to patient-specific patterns of intra-fractional motion.Material and methods. Using four-dimensional computed tomography (4DCT) images of three lung cancer patients we evaluated the impact of the WEPL changes on target dose coverage for a series of coplanar single-beam plans. The plans were optimised for the internal target volume (ITV) at the maximum intensity projection (MIP) CT for every 3° gantry interval. The plans were transferred to the ten 4DCT phases and the average reduction in ITV V95 over the ten phases, relative to the original MIP CT calculation, was quantified. The target dose reduction was associated with the mean difference between the WEPL and the phase-averaged WEPL computed for all beam rays across all possible gantry-couch angle combinations.Results. The gantry-couch angle maps showed areas of both high and low WEPL variation, with overall quite similar patterns yet with individual differences reflecting differences in tumour position and breathing-induced motion. The coplanar plans showed a strong association between WEPL changes and ITV V95 reduction, with a correlation coefficient ranging between 0.92 and 0.98 for the three patients (p < 0.01).Conclusion. We have presented a 4DCT-based method to quantify WEPL changes during the breathing cycle. The method identified proton field gantry-couch angle combinations that were either sensitive or robust to WEPL changes. WEPL variations along the beam path were associated with target under-dosage.

TH‐A‐19A‐03: Impact of Proton Dose Calculation Method On Delivered Dose to Lung Tumors: Experiments in Thorax Phantom and Planning Study in Patient Cohort

Purpose:Evaluate Monte Carlo (MC) dose calculation and the prediction of the treatment planning system (TPS) in a lung phantom and compare them in a cohort of 20 lung patients treated with protons.Methods:A 2‐dimensional array of ionization chambers was used to evaluate the dose across the target in a lung phantom. 20 lung cancer patients on clinical trials were re‐simulated using a validated Monte Carlo toolkit (TOPAS) and compared to the TPS.Results:MC increases dose calculation accuracy in lung compared to the clinical TPS significantly and predicts the dose to the target in the phantom within ±2%: the average difference between measured and predicted dose in a plane through the center of the target is 5.6% for the TPS and 1.6% for MC. MC recalculations in patients show a mean dose to the clinical target volume on average 3.4% lower than the TPS, exceeding 5% for small fields. The lower dose correlates significantly with aperture size and the distance of the tumor to the chest wall (Spearman's p=0.0002/0.004). For large tumors MC also predicts consistently higher V5 and V10 to the normal lung, due to a wider lateral penumbra, which was also observed experimentally. Critical structures located distal to the target can show large deviations, though this effect is very patient‐specific.Conclusion:Advanced dose calculation techniques, such as MC, would improve treatment quality in proton therapy for lung cancer by avoiding systematic overestimation of target dose and underestimation of dose to normal lung. This would increase the accuracy of the relationships between dose and effect, concerning tumor control as well as normal tissue toxicity. As the role of proton therapy in the treatment of lung cancer continues to be evaluated in clinical trials, this is of ever‐increasing importance.This work was supported by National Cancer Institute Grant R01CA111590.

TH‐A‐19A‐10: Fast Four Dimensional Monte Carlo Dose Computations for Proton Therapy of Lung Cancer

Purpose:To develop and validate a fast and accurate four dimensional (4D) Monte Carlo (MC) dose computation system for proton therapy of lung cancer and other thoracic and abdominal malignancies in which the delivered dose distributions can be affected by respiratory motion of the patient.Methods:A 4D computer tomography (CT) scan for a lung cancer patient treated with protons in our clinic was used to create a time dependent patient model using our in‐house, MCNPX‐based Monte Carlo system (“MC2”). The beam line configurations for two passively scattered proton beams used in the actual treatment were extracted from the clinical treatment plan and a set of input files was created automatically using MC2. A full MC simulation of the beam line was computed using MCNPX and a set of phase space files for each beam was collected at the distal surface of the range compensator. The particles from these phase space files were transported through the 10 voxelized patient models corresponding to the 10 phases of the breathing cycle in the 4DCT, using MCNPX and an accelerated (fast) MC code called “FDC”, developed by us and which is based on the track repeating algorithm. The accuracy of the fast algorithm was assessed by comparing the two time dependent dose distributions.Results:The error of less than 1% in 100% of the voxels in all phases of the breathing cycle was achieved using this method with a speedup of more than 1000 times.Conclusion:The proposed method, which uses full MC to simulate the beam line and the accelerated MC code FDC for the time consuming particle transport inside the complex, time dependent, geometry of the patient shows excellent accuracy together with an extraordinary speed.