Proton Therapy For Lung Cancer Research Articles

Comparing interplay effects in scanned proton therapy of lung cancer: Free breathing with various layer and volume rescanning versus respiratory gating with different gate widths

PurposeWe investigated interplay effects and treatment time (TT) in scanned proton therapy for lung cancer patients. We compared free-breathing (FB) approaches with multiple rescanning strategies and respiratory-gating (RG) methods with various gating widths to identify the superior irradiation technique. MethodsPlans were created with 4/1, 2/2, and 1/4 layered/volume rescans of FB (L4V1, L2V2, and L1V4), and 50%, 30%, and 10% gating widths of the total respiratory curves (G50, G30, and G10) of the RG plans with L4V1. We calculated 4-dimensional dynamic doses assuming a constant sinusoidal curve for six irradiation methods. The reconstructed doses per fraction were compared with planned doses in terms of dose differences in 99% clinical-target-volume (CTV) (ΔD99%), near-maximum dose differences (ΔD2%) at organs-at-risk (OARs), and TT. ResultsThe mean/minimum CTV ΔD99% values for FB were −1.0%/−4.9%, −0.8%/−4.3%, and −0.1%/−1.0% for L4V1, L2V2, and L1V4, respectively. Those for RG were −0.3%/−1.7%, −0.1%/−1.0%, and 0.0%/−0.5% for G50, G30, and G10, respectively. The CTV ΔD99% of the RGs with less than 50% gate width and the FBs of L1V4 were within the desired tolerance (±3.0%), and the OARs ΔD2% for RG were lower than those for FB. The mean TTs were 90, 326, 824, 158, 203, and 422 s for L4V1, L2V2, L1V4, G50, G30, and G10, respectively. ConclusionsFB (L4V1) is the most efficient treatment, but not necessarily the optimal choice due to interplay effects. To satisfy both TT extensions and interplay, RG with a gate width as large as possible within safety limits is desirable.

Secondary cancer risk assessments following the proton therapy of lung cancer as the functions of field characteristics and patient age

Introduction Radiation-induced secondary cancers relevant to proton therapy are still a main concern among cancer survivors. This study aims to determine the effects of age at exposure and treatment field size on radiation-induced secondary tumors following the proton therapy of lung cancer within out of field organs through the Monte Carlo (MC) simulation approach. Material and Methods A full MC model of ICRP-110 male phantom was simulated to calculate the absorbed dose corresponding to secondary radiations within distant organs from the tumor volume. Then, the risks of secondary malignancies were estimated by employing the recommended risk model by the Committee of Biological Effects of Ionizing Radiation (BEIR) for different treatment field sizes and various patient ages at exposure. Results The results revealed that by increasing the patient age from 25 to 45 years, lifetime attributable risk (LAR) values were decreased. Maximum and minimum mortality rates were obtained for the liver and thyroid at the fixed age of 25 years, respectively. Calculated risk values for most near organs to the tumor were higher than those for distant organs. Changing the aperture size from 5 × 5 cm2 to 8 × 10 cm2 resulted in LAR increments with maximum variations of 12.5% for the stomach and a rough variation of 1.12 times in LAR for all exposure ages. Conclusion Our work on whole-body phantom addresses the impact of age at exposure and aperture size on LAR during the proton therapy of lung cancer. To minimize secondary cancer risks relevant to proton therapy of lung cancer, extra attention should be considered.

Mapping absorption dose in proton therapy of lung cancer using MCNP-6 code

Simulations by the MCNP6 code for proton therapy succeeded in mapping the absorbed dose in lung cancer. Proton therapy simulation using active scanning method with 9 disc-shaped sources with a diameter of 0.4 cm. Mono directional beams to cancer cells at a depth of 7.9 – 9.4 cm from the skin, while the distance from the skin to the source is 14.35 cm. Cubic cancer cells measuring (1.5 x 1.5 x 1.5) cm3 were scanned by proton beams of 94 MeV and 104 MeV. The position of the largest absorbed dose of proton therapy is the position of the formation of the Bragg peak. Evaluation of the 94 MeV proton beam showed that the Bragg peak was at a depth of 7.65 cm, meaning in front of the cancer position. While in the 104 MeV beam, the Bragg peak is at a depth of 9.15 cm or is behind the position of the placed cancer. This dose is mapped on a cross-sectional graph of cancer cells so that an overview of the dose distribution is obtained in each part of the cancer cell. While the Bragg peak position from irradiation with an energy of 104 MeV fell on the back cancer cells or at a depth of 9.15 cm from the skin surface. From the position of the Bragg peak on the two irradiation energies, it can be concluded that these two energies have not given the optimum dose to cancer cells. We require irradiation with proton energy variations or setting the distance of the source in order to achieve a good isodose in cancer cells.

194P Motion of lymph nodes and the effect on the dose coverage in proton therapy of lung cancer

194P Motion of lymph nodes and the effect on the dose coverage in proton therapy of lung cancer

Scatter correction of 4D cone beam computed tomography to detect dosimetric effects due to anatomical changes in proton therapy for lung cancer.

The treatment of moving tumor entities is expected to have superior clinical outcomes, using image-guided adaptive intensity-modulated proton therapy (IMPT). For 21 lung cancer patients, IMPT dose calculations were performed on scatter-corrected 4D cone beam CTs (4DCBCTcor ) to evaluate their potential for triggering treatment adaptation. Additional dose calculations were performed on corresponding planning 4DCTs and day-of-treatment 4D virtual CTs (4DvCTs). A 4DCBCT correction workflow, previously validated on a phantom, generates 4DvCT (CT-to-CBCT deformable registration) and 4DCBCTcor images (projection-based correction using 4DvCT as a prior) with 10 phase bins, using day-of-treatment free-breathing CBCT projections and planning 4DCT images as input. Using a research planning system, robust IMPT plans administering eight fractions of 7.5 Gy were created on a free-breathing planning CT (pCT) contoured by a physician. The internal target volume (ITV) was overridden with muscle tissue. Robustness settings for range and setup uncertainties were 3% and 6 mm, and a Monte Carlo dose engine was used. On every phase of planning 4DCT, day-of-treatment 4DvCT, and 4DCBCTcor , the dose was recalculated. For evaluation, image analysis as well as dose analysis were performed using mean error (ME) and mean absolute error (MAE) analysis, dose-volume histogram (DVH) parameters, and 2%/2-mm gamma pass rate analysis. Action levels (1.6% ITV D98 and 90% gamma pass rate) based on our previous phantom validation study were set to determine which patients had a loss of dosimetriccoverage. Quality enhancements of 4DvCT and 4DCBCTcor over 4DCBCT were observed. ITV D98% and bronchi D2% had its largest agreement for 4DCBCTcor -4DvCT, and the largest gamma pass rates (>94%, median 98%) were found for 4DCBCTcor -4DvCT. Deviations were larger and gamma pass rates were smaller for 4DvCT-4DCT and 4DCBCTcor -4DCT. For five patients, deviations were larger than the action levels, suggesting substantial anatomical changes between pCT and CBCT projectionsacquisition. This retrospective study shows the feasibility of daily proton dose calculation on 4DCBCTcor for lung tumor patients. The applied method is of clinical interest as it generates up-to-date in-room images, accounting for breathing motion and anatomical changes. This information could be used to triggerreplanning.

Inter- and intrafractional 4D dose accumulation for evaluating ΔNTCP robustness in lung cancer

Background and purposeModel-based selection of proton therapy patients relies on a predefined reduction in normal tissue complication probability (NTCP) with respect to photon therapy. The decision is necessarily made based on the treatment plan, but NTCP can be affected when the delivered treatment deviates from the plan due to delivery inaccuracies. Especially for proton therapy of lung cancer, this can be important because of tissue density changes and, with pencil beam scanning, the interplay effect between the proton beam and breathing motion. Materials and methodsIn this work, we verified whether the expected benefit of proton therapy is retained despite delivery inaccuracies by reconstructing the delivered treatment using log-file based dose reconstruction and inter- and intrafractional accumulation. Additionally, the importance of two uncertain parameters for treatment reconstruction, namely deformable image registration (DIR) algorithm and α/β ratio, was assessed. ResultsThe expected benefit or proton therapy was confirmed in 97% of all studied cases, despite regular differences up to 2 percent point (p.p.) NTCP between the delivered and planned treatments. The choice of DIR algorithm affected NTCP up to 1.6 p.p., an order of magnitude higher than the effect of α/β ratio. ConclusionFor the patient population and treatment technique employed, the predicted clinical benefit for patients selected for proton therapy was confirmed for 97.0% percent of all cases, although the NTCP based proton selection was subject to 2 p.p. variations due to delivery inaccuracies.

Trade-off in healthy tissue sparing of FLASH and fractionation in stereotactic proton therapy of lung lesions with transmission beams.

Besides a dose-rate threshold of 40-100Gy/s, the FLASH effect may require a dose>3.5-7Gy. Even in hypofractioned treatments, with all beams delivered in each fraction (ABEF), most healthy tissue is irradiated to a lower fraction dose. This can be circumvented by single-beam-per-fraction (SBPF) delivery, with a loss of healthy tissue sparing by fractionation. We investigated the trade-off between FLASH and loss of fractionation in SBPF stereotactic proton therapy of lung cancer and determined break-even FLASH-enhancement ratios (FERs). Treatment plans for 12 patients were generated. GTV delineations were available and a 5mm GTV-PTV margin was applied. Equiangular arrangements of 3, 5, 7, and 9 244MeV proton transmission beams were used. To facilitate SBPF, the number of fractions was equal to the number of beams. Iso-effective fractionation schedules with a single field uniform dose prescription were used: D95%,PTV=100%Dpres per beam. All plans were evaluated in terms of dose to lung and conformity of dose to target of FLASH-enhanced biologically equivalent dose (EQD2). Compared to ABEF, SBPF resulted in a median increase of EQD2mean to healthy lung of 56%, 58%, 55% and 54% in plans with 3, 5, 7 and 9 fractions respectively and of 236%, 78%, 50% and 41% in V100% EQD2, quantifying conformity. This can be compensated for by FERs of at least 1.28, 1.32, 1.30 and 1.23 respectively for EQD2mean and 1.29, 1.18, 1.28 and 1.15 for V100%,EQD2. A FLASH effect outweighing the loss of fractionation in SBPF may be achieved in stereotactic lung treatments. The trade-off with fractionation depends on the conditions under which the FLASH effect occurs. Better understanding of the underlying biology and the impact of delivery conditions is needed.

Substantial Sparing of Organs at Risk with Modern Proton Therapy in Lung Cancer, but Altered Breathing Patterns Can Jeopardize Target Coverage.

Simple SummaryTreatment of locally advanced non-small cell lung cancer (LA-NSCLC) is a fine balance between toxicity and cure. Modern proton therapy might offer a more gentle radiation treatment compared to state-of-the-art photon radiotherapy, but is also more susceptible to the influence of breathing motion and anatomical changes. In this study, the influence of such uncertainties on treatment delivery was thoroughly investigated. Modern proton therapy did indeed show potential to reduce the risk of toxicity for the heart and lungs. This potential was maintained under the influence of anatomical and delivery uncertainties. However, changes in breathing motion jeopardized the target dose distribution in a subset of patients. We therefore recommend imaging at onset or early in treatment to recognize these patients and adapt the treatment.Enhancing treatment of locally advanced non-small cell lung cancer (LA-NSCLC) by using pencil beam scanning proton therapy (PBS-PT) is attractive, but little knowledge exists on the effects of uncertainties occurring between the planning (Plan) and the start of treatment (Start). In this prospective simulation study, we investigated the clinical potential for PBS-PT under the influence of such uncertainties. Imaging with 4DCT at Plan and Start was carried out for 15 patients that received state-of-the-art intensity-modulated radiotherapy (IMRT). Three PBS-PT plans were created per patient: 3D robust single-field uniform dose (SFUD), 3D robust intensity-modulated proton therapy (IMPT), and 4D robust IMPT (4DIMPT). These were exposed to setup and range uncertainties and breathing motion at Plan, and changes in breathing motion and anatomy at Start. Target coverage and dose-volume parameters relevant for toxicity were compared. The organ at risk sparing at Plan was greatest with IMPT, followed by 4DIMPT, SFUD and IMRT, and persisted at Start. All plans met the preset criteria for target robustness at Plan. At Start, three patients had a lack of CTV coverage with PBS-PT. In conclusion, the clinical potential for heart and lung toxicity reduction with PBS-PT was substantial and persistent. Altered breathing patterns between Plan and Start jeopardized target coverage for all PBS-PT techniques.

Analysis of dose distribution in proton therapy for lung cancer with MCNP code

Proton beam characteristics for proton therapy have been obtained by simulation method using MCNP6 software. The proton beam is modelled as a monodirectional disk with a diameter of 3 cm is 23 cm from the left lung cancer, a sphere with a diameter of 3 cm. The variation of proton beam energy that produces the best isodose in cancer cells is 94 MeV, 104 MeV, and 112 MeV fired alternately at the target from the left. The result is a total equivalent dose in cancer cells of (0.858 ± 0.003) Sv. The scattered amount received by healthy cells in the left lung was (1.39 ± 0.01) mSv, rib (0.12 ± 0.01) mSv, and skin (0.11 ± 0.01) mSv. According to the organ at risk (OAR) provisions, the scattered dose is declared safe. The simulation results prove that proton therapy is a cell targeting therapy. The dose used to kill lung cancer cells is 60 Gy, so with a proton beam of 1 µA, the total exposure time for therapy is (2.31 ± 0.01) minutes.

Clinical suitability of deep learning based synthetic CTs for adaptive proton therapy of lung cancer.

PurposeAdaptive proton therapy (APT) of lung cancer patients requires frequent volumetric imaging of diagnostic quality. Cone‐beam CT (CBCT) can provide these daily images, but x‐ray scattering limits CBCT‐image quality and hampers dose calculation accuracy. The purpose of this study was to generate CBCT‐based synthetic CTs using a deep convolutional neural network (DCNN) and investigate image quality and clinical suitability for proton dose calculations in lung cancer patients.MethodsA dataset of 33 thoracic cancer patients, containing CBCTs, same‐day repeat CTs (rCT), planning‐CTs (pCTs), and clinical proton treatment plans, was used to train and evaluate a DCNN with and without a pCT‐based correction method. Mean absolute error (MAE), mean error (ME), peak signal‐to‐noise ratio, and structural similarity were used to quantify image quality. The evaluation of clinical suitability was based on recalculation of clinical proton treatment plans. Gamma pass ratios, mean dose to target volumes and organs at risk, and normal tissue complication probabilities (NTCP) were calculated. Furthermore, proton radiography simulations were performed to assess the HU‐accuracy of sCTs in terms of range errors.ResultsOn average, sCTs without correction resulted in a MAE of 34 ± 6 HU and ME of 4 ± 8 HU. The correction reduced the MAE to 31 ± 4HU (ME to 2 ± 4HU). Average 3%/3 mm gamma pass ratios increased from 93.7% to 96.8%, when the correction was applied. The patient specific correction reduced mean proton range errors from 1.5 to 1.1 mm. Relative mean target dose differences between sCTs and rCT were below ± 0.5% for all patients and both synthetic CTs (with/without correction). NTCP values showed high agreement between sCTs and rCT (<2%).ConclusionCBCT‐based sCTs can enable accurate proton dose calculations for APT of lung cancer patients. The patient specific correction method increased the image quality and dosimetric accuracy but had only a limited influence on clinically relevant parameters.

TCP and NTCP Calculations Based on Treatment Doses Instead of Planned Doses for Daily Adaptive Proton Therapy of Lung Cancer

Calculation of tumor control probability (TCP) and normal tissue complication probability (NTCP) is becoming increasingly relevant for optimizing treatment strategies, for example the selection of patients for proton therapy. While radiobiological models are typically built and evaluated on the planned treatment dose, no consensus exists for their evaluation in the context of varying patient anatomy during treatment. For example, different adaptive strategies can lead to different expected treatment outcomes for the same planned dose. This shows that TCP/NTCP needs to be calculated from the cumulative treatment dose resulting from multiple fraction doses and patient geometries. In this study, different methods of applying TCP and NTCP models to treatments with anatomical changes are developed and compared. These methods were evaluated on an example of locally advanced non-small cell lung cancer (NSCLC) patients using two extreme scenarios: no adaption vs online daily adaptive proton therapy (DAPT).Three methods to calculate TCP/NTCP in the context of anatomical changes were compared: (I) based on the accumulated treatment doses. Six different deformable image registration (DIR) algorithms were used to accumulate the dose, then the TCP/NTCP was calculated on all accumulated doses showing the variation due to the DIR. (II) based on the cumulative effective uniform dose (EUD) of each fraction. (III) based on each fraction dose directly, permitting an evaluation of the mean and variation of TCP/NTCP during treatment. To test and compare these methods, proton therapy treatment plans were generated on deep inspiration breath-hold (DIBH) planning CTs for 5 NSCLC patients (66 Gy-RBE, 33 fractions). Non-adapted and DAPT treatment doses were created by recalculating and reoptimizing these plans on nine repeated CTs. TCP/NTCP calculations were performed with all three methods.All methods showed consistent results between no adaption and DAPT. Two patients showed substantial TCP reductions up to 33% without adaption. Three patients, despite anatomical changes and dose differences, did not show a reduced calculated TCP with all methods. For most patients, NTCP differences between DAPT and no adaption were moderate, but one showed improvement in predicted 2-year survival based on heart toxicity with DAPT. Furthermore, the absolute NTCP calculated with method (I) showed variations of up to 7% depending on the DIR algorithm used for dose accumulation.The three proposed methods of calculating clinical outcome based on treatment doses showed consistent result between DAPT and non-adapted treatments. Three patients showed benefits with DAPT, so the calculated NTCP could be reduced or calculated TCP maintained. For two patients the dose differences with adaption did not translate in clinically relevant effects. The proposed outcome calculation methods enable a more realistic quantification of TCP/NTCP of different adaptive strategies.

OC-0478 Neural network based synthetic CTs for adaptive proton therapy of lung cancer

OC-0478 Neural network based synthetic CTs for adaptive proton therapy of lung cancer

An approach for estimating dosimetric uncertainties in deformable dose accumulation in pencil beam scanning proton therapy for lung cancer

Deformable image registration (DIR) is an important component for dose accumulation and associated clinical outcome evaluation in radiotherapy. However, the resulting deformation vector field (DVF) is subject to unavoidable discrepancies when different algorithms are applied, leading to dosimetric uncertainties of the accumulated dose. We propose here an approach for proton therapy to estimate dosimetric uncertainties as a consequence of modeled or estimated DVF uncertainties. A patient-specific DVF uncertainty model was built on the first treatment fraction, by correlating the magnitude differences of five DIR results at each voxel to the magnitude of any single reference DIR. In the following fractions, only the reference DIR needs to be applied, and DVF geometric uncertainties were estimated by this model. The associated dosimetric uncertainties were then derived by considering the estimated geometric DVF uncertainty, the dose gradient of fractional recalculated dose distribution and the direction factor from the applied reference DIR of this fraction. This estimated dose uncertainty was respectively compared to the reference dose uncertainty when different DIRs were applied individually for each dose warping. This approach was validated on seven NSCLC patients, each with nine repeated CTs. The proposed model-based method is able to achieve dose uncertainty distribution on a conservative voxel-to-voxel comparison within ±5% of the prescribed dose to the ‘reference’ dosimetric uncertainty, for 77% of the voxels in the body and 66%–98% of voxels in investigated structures. We propose a method to estimate DIR induced uncertainties in dose accumulation for proton therapy of lung tumor treatments.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

Impact of Multiple Beams on Plan Quality, Linear Energy Transfer Distribution, and Plan Robustness of Intensity Modulated Proton Therapy for Lung Cancer.

The increase of proton beam number might provide higher degrees of freedom in the optimization of intensity-modulated proton therapy planning. In this study, we aimed to quantitatively explore the potential benefits of the increased beam number, including dose volume histogram (DVH), linear energy transfer volume histogram, and DVH bandwidth metrics. Twelve patients with lung cancer are retrospectively selected. Four plans were created based on internal target volume (ITV) robust optimization for each patient using the RayStation treatment planning system. Four plans were generated using different numbers (three, five, seven, and nine) of evenly separated coplanar beams. The three-beam plan was considered as the reference plan. Biologically equivalent doses were calculated using both constant relative biological effectiveness (RBE) and variable RBE models, respectively. To evaluate plan quality, DVH metrics in the target [ITV: D2%, CI, HI] and organs-at-risk [Lung: V5Gy[RBE], V20Gy[RBE], V30Gy[RBE]; Heart D2%; Spinal cord D2%] were calculated using both RBE models. To evaluate LET distributions, LET volume histogram metrics [ITV LETmean and LET2%; Lung LETmean and LET2%; Heart LET2%; Spinal cord LET2%] were quantified. To evaluate plan robustness, the metrics using DVH bandwidth [ITV: D2%, D99%; Lung: V5Gy[RBE], V20Gy[RBE], V30Gy[RBE]; Heart D2%; Spinal cord D2%] were also reported. For plan quality, the increase of proton beam number resulted in fewer target hot spots, improved target dose conformity, improved target dose homogeneity, lower median-dose lung volume, and fewer hot spots in spinal cord. As to LET distributions, target mean LET increased significantly as the beam number increased to seven or more. Lung LET hot spots were significantly reduced with the increase of proton beams. With respect to plan robustness, the robustness of target dose coverage, target hot spots, and low-dose lung volume were improved, while the robustness of heart hot spots became worse as the beam number increased to nine. The robustness of cord hot spots became worse using five and seven beams compared to that using three beams. As the proton beam number increased, plan quality and LET distributions were comparable or significantly improved. The robustness of target dose coverage, target dose hot spots, and low-dose lung volume were significantly improved.

Online adaptive dose restoration in intensity modulated proton therapy of lung cancer to account for inter-fractional density changes.

In proton therapy, inter-fractional density changes can severely compromise the effective delivery of the planned dose. Such dose distortion effects can be accounted for by treatment plan adaptation, that requires considerable automation for widespread implementation in clinics. In this study, the clinical benefit of an automatic online adaptive strategy called dose restoration (DR) was investigated. Our objective was to assess to what extent DR could replace the need for a comprehensive offline adaptive strategy. The fully automatic and robust DR workflow was evaluated in a cohort of 14 lung IMPT patients that had a planning-CT and two repeated 4D-CTs (rCT1,rCT2). Initial plans were generated using 4D-robust optimization (including breathing-motion, setup and range errors). DR relied on isodose contours generated from the initial dose and associated patient specific weighted objectives to mimic this initial dose in repeated-CTs. These isodose contours, with their corresponding objectives, were used during re-optimization to compensate proton range distortions disregarding re-contouring. Robustness evaluations were performed for the initial, not-adapted and restored (adapted) plans. The resulting DVH-bands showed overall improvement in DVH metrics and robustness levels for restored plans, with respect to not-adapted plans. According to CTV coverage criteria (D95%>95%Dprescription) in not-adapted plans, 35% (5/14) of the cases needed offline adaptation. After DR, Median(D95%) was increased by 1.1 [IQR,0.4] Gy and only one patient out of 14 (7%) still needed offline adaptation because of important anatomical changes. DR has the potential to improve CTV coverage and reduce offline adaptation rate.

ES16.01 Proton Therapy

Proton therapy is an attractive option for the treatment of lung cancer patients due to the physical properties of proton beams. Proton therapy allows a focused delivery of radiation at the Bragg peak, with very steep decline of the radiation dose beyond the target volume. These properties offer the possibility to 1) reduce toxicity by reducing the integral dose and the dose to adjacent normal tissues and 2) escalate the dose to the target in some patients. In this talk, I will summarise briefly the physics/radiobiology of protons and the need for adaptation. I will also discuss the rationale for the use of protons in patients with lung cancer, including reduction in integral dose, cardiac toxicity and reduction in haematological toxicity. The clinical trial evidence supporting the use of protons will be presented in early stage and locally advanced non-small cell lung cancer as well as in small-cell lung cancer. Finally I will discuss future research directions, including preclinical and drug-proton combination research, ongoing clinical trials, the model based-approach and the need for biomarkers. Liao Z, Lee JJ, Komaki R, eat l. Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36(18):1813-1822 Chang JY, Jabbour SK, De Ruysscher D, et al; International Particle Therapy Co-operative Group Thoracic Subcommittee.Consensus Statement on Proton Therapy in Early-Stage and Locally Advanced Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2016;95(1):505-16. Vyfhuis MAL, Onyeuku N, Diwanji T, Mossahebi S, Amin NP, Badiyan SN, Mohindra P, Simone CB 2nd. Advances in proton therapy in lung cancer. Ther Adv Respir Dis. 2018 Jan-Dec;12:1753466618783878 C, Pawelke J, Seidlitz A, Peitzsch C, et al; “Radiobiology of Proton Therapy”: Results of an international expert workshop.Lühr A, von Neubeck Radiother Oncol. 2018; 128(1):56-67 Jin, J.Y., et al., Higher Radiation Dose to Immune System is Correlated With Poorer Survival in Patients With Stage III Non-small Cell Lung Cancer: A Secondary Study of a Phase 3 Cooperative Group Trial (NRG Oncology RTOG 0617). International Journal of Radiation Oncology Biology Physics, 2017. 99(2): p. S151-S152. Joseph, N., et al., Post-treatment lymphocytopaenia, integral body dose and overall survival in lung cancer patients treated with radical radiotherapy. Radiotherapy and Oncology, 2019. 135: p. 115-119. Durante, M., D.J. Brenner, and S.C. Formenti, Does Heavy Ion Therapy Work Through the Immune System? Int J Radiat Oncol Biol Phys, 2016. 96(5): p. 934-936. Lee, H.J., Jr., J. Zeng, and R. Rengan, Proton beam therapy and immunotherapy: an emerging partnership for immune activation in non-small cell lung cancer. Translational lung cancer research, 2018. 7(2): p. 180-188. Dess, R.T., et al., Cardiac Events After Radiation Therapy: Combined Analysis of Prospective Multicenter Trials for Locally Advanced Non-Small-Cell Lung Cancer. J Clin Oncol, 2017. 35(13): p. 1395-1402. McWilliam, A., et al., Radiation dose to heart base linked with poorer survival in lung cancer patients. Eur J Cancer, 2017. 85: p. 106-113. Schulz-Ertner, D. and H. Tsujii, Particle radiation therapy using proton and heavier ion beams. J Clin Oncol, 2007. 25(8): p. 953-64. Gameiro, S.R., et al., Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell-Mediated Killing. Int J Radiat Oncol Biol Phys, 2016. 95(1): p. 120-30.

Organ sparing potential and inter-fraction robustness of adaptive intensity modulated proton therapy for lung cancer

Background: The aim of this study was to compare adaptive intensity modulated proton therapy (IMPT) robustness and organ sparing capabilities with that of adaptive volumetric arc photon therapy (VMAT).Material and methods: Eighteen lung cancer patients underwent a planning 4DCT (p4DCT) and 5 weekly repeated 4DCT (r4DCT) scans. Target volumes and organs at risk were manually delineated on the three-dimensional (3D) average scans of the p4DCT (av_p4DCT) and of the r4DCT scans (av_r4DCT). Planning target volume (PTV)-based VMAT plans and internal clinical target volume (ICTV)-based robust IMPT plans were optimized in 3D on the av_p4DCT and re-calculated on the av_r4DCTs. Re-planning on av_r4DCTs was performed when indicated and accumulated doses were evaluated on the av_p4DCT.Results: Adaptive VMAT and IMPT resulted in adequate ICTV coverage on av_r4DCT in all patients and adequate accumulated-dose ICTV coverage on av_p4DCT in 17/18 patients (due to a shrinking target in one patient). More frequent re-planning was needed for IMPT than for VMAT. The average mean heart dose reduction with IMPT compared with VMAT was 4.6 Gy (p = .001) and it was >5 Gy for five patients (6, 7, 8, 15, and 22 Gy). The average mean lung dose reduction was 3.2 Gy (p < .001). Significant reductions in heart and lung V5 Gy were observed with IMPT.Conclusion: Robust-planned IMPT required re-planning more often than VMAT but resulted in similar accumulated ICTV coverage. With IMPT, heart and lung mean dose values and low dose regions were significantly reduced. Substantial cardiac sparing was obtained in a subgroup of five patients (28%).

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