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.

Liu W ，Schild SE ，Chang JY ，Liao Z ，Chang YH ，Wen Z ，Shen J ，Stoker JB ，Ding X ，Hu Y ，Sahoo N ，Herman MG ，Vargas C ，Keole S ，Wong W ，Bues M ... -  《-》

Technical Note: Treatment planning system (TPS) approximations matter - comparing intensity-modulated proton therapy (IMPT) plan quality and robustness between a commercial and an in-house developed TPS for nonsmall cell lung cancer (NSCLC).

Approximate dose calculation methods were used in the nominal dose distribution and the perturbed dose distributions due to uncertainties in a commercial treatment planning system (CTPS) for robust optimization in intensity-modulated proton therapy (IMPT). We aimed to investigate whether the approximations influence plan quality, robustness, and interplay effect of the resulting IMPT plans for the treatment of locally advanced lung cancer patients. Ten consecutively treated locally advanced nonsmall cell lung cancer (NSCLC) patients were selected. Two IMPT plans were created for each patient using our in-house developed TPS, named "Solo," and also the CTPS, EclipseTM (Varian Medical Systems, Palo Alto, CA, USA), respectively. The plans were designed to deliver prescription doses to internal target volumes (ITV) drawn by a physician on averaged four-dimensional computed tomography (4D-CT). Solo plans were imported back to CTPS, and recalculated in CTPS for fair comparison. Both plans were further verified for each patient by recalculating doses in the inhalation and exhalation phases to ensure that all plans met clinical requirements. Plan robustness was quantified on all phases using dose-volume-histograms (DVH) indices in the worst-case scenario. The interplay effect was evaluated for every plan using an in-house developed software, which randomized starting phases of each field per fraction and accumulated dose in the exhalation phase based on the patient's breathing motion pattern and the proton spot delivery in a time-dependent fashion. DVH indices were compared using Wilcoxon rank-sum test. Compared to the plans generated using CTPS on the averaged CT, Solo plans had significantly better target dose coverage and homogeneity (normalized by the prescription dose) in the worst-case scenario [ITV D95% : 98.04% vs 96.28%, Solo vs CTPS, P = 0.020; ITV D5% -D95% : 7.20% vs 9.03%, P = 0.049] while all DVH indices were comparable in the nominal scenario. On the inhalation phase, Solo plans had better target dose coverage and cord Dmax in the nominal scenario [ITV D95% : 99.36% vs 98.45%, Solo vs CTPS, P = 0.014; cord Dmax : 20.07 vs 23.71 Gy(RBE), P = 0.027] with better target coverage and cord Dmax in the worst-case scenario [ITV D95% : 97.89% vs 96.47%, Solo vs CTPS, P = 0.037; cord Dmax : 24.57 vs 28.14 Gy(RBE), P = 0.037]. On the exhalation phase, similar phenomena were observed in the nominal scenario [ITV D95% : 99.63% vs 98.87%, Solo vs CTPS, P = 0.037; cord Dmax : 19.67 vs 23.66 Gy(RBE), P = 0.039] and in the worst-case scenario [ITV D95% : 98.20% vs 96.74%, Solo vs CTPS, P = 0.027; cord Dmax : 23.47 vs 27.93 Gy(RBE), P = 0.027]. In terms of interplay effect, plans generated by Solo had significantly better target dose coverage and homogeneity, less hot spots, and lower esophageal Dmean , and cord Dmax [ITV D95% : 101.81% vs 98.68%, Solo vs CTPS, P = 0.002; ITV D5% -D95% : 2.94% vs 7.51%, P = 0.002; cord Dmax : 18.87 vs 22.29 Gy(RBE), P = 0.014]. Solo-generated IMPT plans provide improved cord sparing, better target robustness in all considered phases, and reduced interplay effect compared with CTPS. Consequently, the approximation methods currently used in commercial TPS programs may have space for improvement in generating optimal IMPT plans for patient cases with locally advanced lung cancer.

Liu C ，Yu NY ，Shan J ，Bhangoo RS ，Daniels TB ，Chiang JS ，Ding X ，Lara P ，Patrick CL ，Archuleta JP ，DeWees T ，Hu Y ，Schild SE ，Bues M ，Sio TT ，Liu W ... -  《-》

Impact of Spot Size and Spacing on the Quality of Robustly Optimized Intensity Modulated Proton Therapy Plans for Lung Cancer.

To investigate how spot size and spacing affect plan quality, robustness, and interplay effects of robustly optimized intensity modulated proton therapy (IMPT) for lung cancer. Two robustly optimized IMPT plans were created for 10 lung cancer patients: first by a large-spot machine with in-air energy-dependent large spot size at isocenter (σ: 6-15 mm) and spacing (1.3 σ), and second by a small-spot machine with in-air energy-dependent small spot size (σ: 2-6 mm) and spacing (5 mm). Both plans were generated by optimizing radiation dose to internal target volume on averaged 4-dimensional computed tomography scans using an in-house-developed IMPT planning system. The dose-volume histograms band method was used to evaluate plan robustness. Dose evaluation software was developed to model time-dependent spot delivery to incorporate interplay effects with randomized starting phases for each field per fraction. Patient anatomy voxels were mapped phase-to-phase via deformable image registration, and doses were scored using in-house-developed software. Dose-volume histogram indices, including internal target volume dose coverage, homogeneity, and organs at risk (OARs) sparing, were compared using the Wilcoxon signed-rank test. Compared with the large-spot machine, the small-spot machine resulted in significantly lower heart and esophagus mean doses, with comparable target dose coverage, homogeneity, and protection of other OARs. Plan robustness was comparable for targets and most OARs. With interplay effects considered, significantly lower heart and esophagus mean doses with comparable target dose coverage and homogeneity were observed using smaller spots. Robust optimization with a small spot-machine significantly improves heart and esophagus sparing, with comparable plan robustness and interplay effects compared with robust optimization with a large-spot machine. A small-spot machine uses a larger number of spots to cover the same tumors compared with a large-spot machine, which gives the planning system more freedom to compensate for the higher sensitivity to uncertainties and interplay effects for lung cancer treatments.

Liu C ，Schild SE ，Chang JY ，Liao Z ，Korte S ，Shen J ，Ding X ，Hu Y ，Kang Y ，Keole SR ，Sio TT ，Wong WW ，Sahoo N ，Bues M ，Liu W ... -  《-》

Intensity-modulated proton therapy (IMPT) interplay effect evaluation of asymmetric breathing with simultaneous uncertainty considerations in patients with non-small cell lung cancer.

Intensity-modulated proton therapy (IMPT) is sensitive to uncertainties from patient setup and proton beam range, as well as interplay effect. In addition, respiratory motion may vary from cycle to cycle, and also from day to day. These uncertainties can severely degrade the original plan quality and potentially affect patient's outcome. In this work, we developed a new tool to comprehensively consider the impact of all these uncertainties and provide plan robustness evaluation under them. We developed a comprehensive plan robustness evaluation tool that considered both uncertainties from patient setup and proton beam range, as well as respiratory motion simultaneously. To mimic patients' respiratory motion, the time spent in each phase was randomly sampled based on patient-specific breathing pattern parameters as acquired during the four-dimensional (4D)-computed tomography (CT) simulation. Spots were then assigned to one specific phase according to the temporal relationship between spot delivery sequence and patients' respiratory motion. Dose in each phase was calculated by summing contributions from all the spots delivered in that phase. The final 4D dynamic dose was obtained by deforming all doses in each phase to the maximum exhalation phase. Three hundred (300) scenarios (10 different breathing patterns with 30 different setup and range uncertainty scenario combinations) were calculated for each plan. The dose-volume histograms (DVHs) band method was used to assess plan robustness. Benchmarking the tool as an application's example, we compared plan robustness under both three-dimensional (3D) and 4D robustly optimized IMPT plans for 10 nonrandomly selected patients with non-small cell lung cancer. The developed comprehensive plan robustness tool had been successfully applied to compare the plan robustness between 3D and 4D robustly optimized IMPT plans for 10 lung cancer patients. In the presence of interplay effect with uncertainties considered simultaneously, 4D robustly optimized plans provided significantly better CTV coverage (D95% , P = 0.002), CTV homogeneity (D5% -D95% , P = 0.002) with less target hot spots (D5% , P = 0.002), and target coverage robustness (CTV D95% bandwidth, P = 0.004) compared to 3D robustly optimized plans. Superior dose sparing of normal lung (lung Dmean , P = 0.020) favoring 4D plans and comparable normal tissue sparing including esophagus, heart, and spinal cord for both 3D and 4D plans were observed. The calculation time for all patients included in this study was 11.4 ± 2.6 min. A comprehensive plan robustness evaluation tool was successfully developed and benchmarked for plan robustness evaluation in the presence of interplay effect, setup and range uncertainties. The very high efficiency of this tool marks its clinical adaptation, highly practical and versatile nature, including possible real-time intra-fractional interplay effect evaluation as a potential application for future use.

Shan J ，Yang Y ，Schild SE ，Daniels TB ，Wong WW ，Fatyga M ，Bues M ，Sio TT ，Liu W ... -  《-》

Technical Note: 4D robust optimization in small spot intensity-modulated proton therapy (IMPT) for distal esophageal carcinoma.

To compare the dosimetric performances of small-spot three-dimensional (3D) and four-dimensional (4D) robustly optimized intensity-modulated proton (IMPT) plans in the presence of uncertainties and interplay effect simultaneously for distal esophageal carcinoma. Thirteen (13) patients were selected and re-planned with small-spot ( σ  ~ 2-6 mm) 3D and 4D robust optimization in IMPT, respectively. The internal clinical target volumes (CTVhigh3d , CTVlow3d ) were used in 3D robust optimization. Different CTVs (CTVhigh4d , CTVlow4d ) were generated by subtracting an inner margin of the motion amplitudes in three cardinal directions from the internal CTVs and used in 4D robust optimization. All patients were prescribed the same dose to CTVs (50 Gy[RBE] for CTVhigh3d /CTVhigh4d and 45 Gy[RBE] for CTVlow3d /CTVlow4d ). Dose-volume histogram (DVH) indices were calculated to assess plan quality. Comprehensive plan robustness evaluations that consisted of 300 perturbed scenarios (10 different motion patterns to consider irregular motion (sampled from a Gaussian distribution) and 30 different uncertainties scenarios (sampled from a 4D uniform distribution) combined), were performed to quantify robustness to uncertainties and interplay effect simultaneously. Wilcoxon signed-rank test was used for statistical analysis. Compared to 3D robustly optimized plans, 4D robustly optimized plans had statistically improved target coverage and better sparing of lungs and heart (heart Dmean , P = 0.001; heart V30Gy[RBE] , P = 0.001) in the nominal scenario. 4D robustly optimized plans had better robustness in target dose coverage (CTVhigh4d V100% , P = 0.002) and the protection of lungs and heart (heart Dmean , P = 0.001; heart V30Gy[RBE] , P = 0.001) when uncertainties and interplay effect were considered simultaneously. Even with small spots in IMPT, 4D robust optimization outperformed 3D robust optimization in terms of normal tissue protection and robustness to uncertainties and interplay effect simultaneously. Our findings support the use of 4D robust optimization to treat distal esophageal carcinoma with small spots in IMPT.

Feng H ，Shan J ，Ashman JB ，Rule WG ，Bhangoo RS ，Yu NY ，Chiang J ，Fatyga M ，Wong WW ，Schild SE ，Sio TT ，Liu W ... -  《-》