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Background The interaction between breathing motion and scanning beams causes interplay effects in spot-scanning proton therapy for lung cancer, resulting in compromised treatment quality. This study investigated the effects and clinical robustness of two types of spot-scanning proton therapy with motion-mitigation techniques for locally advanced non-small cell lung cancer (NSCLC) using a new simulation tool (4DCT-based dose reconstruction). Methods Three-field single-field uniform dose (SFUD) and robustly optimized intensity-modulated proton therapy (IMPT) plans combined with gating and re-scanning techniques were created using a VQA treatment planning system for 15 patients with locally advanced NSCLC (70 GyRBE/35 fractions). In addition, gating windows of three or five phases around the end-of-expiration phase and two internal gross tumor volumes (iGTVs) were created, and a re-scanning number of four was used. First, the static dose (SD) was calculated using the end-of-expiration computed tomography (CT) images. The four-dimensional dynamic dose (4DDD) was then calculated using the SD plans, 4D-CT images, and the deformable image registration technique on end-of-expiration CT. The target coverage (V 98%, V 100% ), homogeneity index (HI), and conformation number (CN) for the iGTVs and organ-at-risk (OAR) doses were calculated for the SD and 4DDD groups and statistically compared between the SD, 4DDD, SFUD, and IMPT treatment plans using paired t-test. Results In the 3- and 5-phase SFUD, statistically significant differences between the SD and 4DDD groups were observed for V 100% , HI, and CN. In addition, statistically significant differences were observed for V 98% , V 100% , and HI in phases 3 and 5 of IMPT. The mean V 98% and V 100% in both 3-phase plans were within clinical limits (> 95%) when interplay effects were considered; however, V 100% decreased to 89.3% and 94.0% for the 5-phase SFUD and IMPT, respectively. Regarding the significant differences in the deterioration rates of the dose volume histogram (DVH) indices, the 3-phase SFUD plans had lower V 98% and CN values and higher V 100% values than the IMPT plans. In the 5-phase plans, SFUD had higher deterioration rates for V 100% and HI than IMPT. Conclusions Interplay effects minimally impacted target coverage and OAR doses in SFUD and robustly optimized IMPT with 3-phase gating and re-scanning for locally advanced NSCLC. However, target coverage significantly declined with an increased gating window. Robustly optimized IMPT showed superior resilience to interplay effects, ensuring better target coverage, prescription dose adherence, and homogeneity than SFUD. Trial registration : None.

Background Esophageal carcinoma is the eighth most common cancer in the world. Volumetric‐modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small‐spot intensity‐modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small‐spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects. Methods 35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small‐spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase‐averaged 4D‐CT's. The dose‐volume‐histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank‐sum test. For fair comparison, all the treatment plans were normalized to have the same CTVhigh D95% in the nominal scenario relative to the prescription dose. Results In the nominal scenario, small‐spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE], lung Dmean, heart Dmean compared with VMAT. CTVhigh dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE], liver V30Gy[RBE], stomach V45Gy[RBE], lung Dmean, V5Gy[RBE], and V20Gy[RBE], cord Dmax and D0.03cm3, liver Dmean, heart V20Gy[RBE], and V30Gy[RBE], but IMPT was significantly worse for CTVhigh D95%, D2cm3, and D5%‐D95%, CTVlow D95%, heart Dmean, and V40Gy[RBE], requiring careful and experienced adjustments during the planning process and robustness considerations. The small‐spot IMPT plans still met the standard clinical requirements after interplay effects were considered. Conclusions Small‐spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small‐spot IMPT for the treatment of distal esophageal carcinoma.

Purpose The interplay effect between dynamic pencil proton beams and motion of the lung tumor presents a challenge in treating lung cancer patients in pencil beam scanning (PBS) proton therapy. The main purpose of the current study was to investigate the interplay effect on the volumetric repainting lung plans with beam delivery in alternating order (“down” and “up” directions), and explore the number of volumetric repaintings needed to achieve acceptable lung cancer PBS proton plan. Method The current retrospective study included ten lung cancer patients. The total dose prescription to the clinical target volume (CTV) was 70 Gy(RBE) with a fractional dose of 2 Gy(RBE). All treatment plans were robustly optimized on all ten phases in the 4DCT data set. The Monte Carlo algorithm was used for the 4D robust optimization, as well as for the final dose calculation. The interplay effect was evaluated for both the nominal (i.e., without repainting) as well as volumetric repainting plans. The interplay evaluation was carried out for each of the ten different phases as the starting phases. Several dosimetric metrics were included to evaluate the worst‐case scenario (WCS) and bandwidth based on the results obtained from treatment delivery starting in ten different breathing phases. Results The number of repaintings needed to meet the criteria 1 (CR1) of target coverage (D95% ≥ 98% and D99% ≥ 97%) ranged from 2 to 10. The number of repaintings needed to meet the CR1 of maximum dose (ΔD1% < 1.5%) ranged from 2 to 7. Similarly, the number of repaintings needed to meet CR1 of homogeneity index (ΔHI < 0.03) ranged from 3 to 10. For the target coverage region, the number of repaintings needed to meet CR1 of bandwidth (<100 cGy) ranged from 3 to 10, whereas for the high‐dose region, the number of repaintings needed to meet CR1 of bandwidth (<100 cGy) ranged from 1 to 7. Based on the overall plan evaluation criteria proposed in the current study, acceptable plans were achieved for nine patients, whereas one patient had acceptable plan with a minor deviation. Conclusion The number of repaintings required to mitigate the interplay effect in PBS lung cancer (tumor motion < 15 mm) was found to be highly patient dependent. For the volumetric repainting with an alternating order, a patient‐specific interplay evaluation strategy must be adopted. Determining the optimal number of repaintings based on the bandwidth and WCS approach could mitigate the interplay effect in PBS lung cancer treatment.

An understanding of regulating factors and early warning of Ulva prolifera biomass increase may reduce harm or prevent bloom disasters in the Yellow Sea. We investigated the minimum nutrient concentration and light-limiting depth (Z lim) for the growth of floating U. prolifera thalli. Bioavailable dissolved nitrogen (BDN) concentrations in most parts of the study area were almost always higher than the minimum N concentrations required for the growth of floating thalli, indicating no N limitation for the growth of floating thalli. However, the minimum N concentration required for the development of germlings into thalli was higher than BDN in the majority of the area north of 35° N. This indicated that germlings floating out of Subei Shoal were unable to grow into thalli because of N limitation. The minimum P concentration required for germling development was higher than the total dissolved P north of 35° N. This suggested that P limitation occurred for germlings floating out of Subei Shoal. The Z lim for the floating thalli was <0.1 m in most parts of Subei Shoal, which explained why the rapid growth of floating thalli only occurred when they floated out from the Subei Shoal. A grid pattern with the phased multiple increase in biomass per day was designed to predict the possible accumulated multiple increase in biomass (AcMp) when U. prolifera drifted northward following different trajectories. The predicted AcMp values in 2017, 2010, and 2009 were close to the ratio of the coverage area from remote sensing data. Such a grid pattern facilitates quick decisions in disaster prevention and reduction.

Purpose Precise dose delivery to the target is constrained by respiratory motion in intensity modulated proton therapy (IMPT) for lung cancer. This study aims to investigate the impact of treatment planning parameters on the lung cancer IMPT. Materials and methods 30 lung cancer patients treated at Shandong Cancer Hospital and institute were recruited in the study. A 4DCT dataset with 10 respiratory phases was reconstructed for each patient. The RayStation11B treatment planning system was used to create two-oblique-field IMPT plans. A prescription dose of 60 Gy (RBE) for 30 fractions was administered to 95% volume of the CTV. Five proton planning strategies were developed for each patient: (1) Range shifter (RS) plan: four plans were generated by varying range shifter thickness (0, 2, 3, and 5 cm) to change spot sizes; (2) Layer Spacing (LS) plan: four plans with different layer spacing (0.5, 1, 1.5 and 2 cm); (3) Spot Spacing (SS) plan: four plans with spot spacing variations (0.5, 1, 1.5 and 2 cm); (4) Repainting (RE) plan: layer repainting techniques with different numbers of repainting 1, 4 or 8 was adopted to the plan; (5) Ring plan: Dose fall-off was optimized using a ring structure around the target. 4D dynamic dose distributions (4DDDs) were calculated for plans created with various treatment planning parameters. Plan quality and dose-volume histogram (DVH) parameters for the target and organs at risk (OARs) were then analyzed. Results For the RS plan, the D 95% of CTV, V 20 and V 5 of ipsilateral lung increased as the spot size became larger. The D 2% in RS5 plan was slightly higher than in the other three groups. The D 95% and D 2% in the target decreased as the layer spacing increased. The average value for the ELS2 group was about 3.8 Gy (RBE) higher than that of the ELS0.5 group (69.7 vs. 65.9 Gy (RBE)). The values for V 20 and V 5 of lung were similar across groups. Variations in spot spacing had slightly impact on D 95% for the target and V 20 , V 5 for the ipsilateral lung. The effect on D 2% was more pronounced. The median D 95% values for the three groups gradually increased with the number of repainting. For the ipsilateral lung, the number of repainting had little impact on the doses of V 20 and V 5 . For the ring plan, the nominal group had slightly higher D 95% , V 20 , and V 5 values compared to the ring group. The D 2% in the nominal group was lower than that in the ring group, with average values of 65.8 and 67.6 Gy (RBE), respectively. Conclusion A systematic analysis was conducted in this study on the impact of spot size, LS, SS, layer repainting, and ring structure on the 4D robustness of IMPT plans for lung cancer patients. These five strategies demonstrated that beam spot size and layer spacing affected plan robustness, while spot spacing had relatively minor influence on robustness. The repainting technology can mitigate the interplay effect caused by respiratory motion. The application of ring structures affected the dose distribution of the moving target.

Propose Proton therapy of esophageal cancer is beneficial to spare normal tissue in clinical practice. However, intra-fractional and inter-fractional variance of tumor motion during treatment may compromise target coverage. The purpose of this study was to investigate the interplay effect due to intra-fractional motion and the effect of the robust optimization parameters for inter-fractional motion in the intensity modulation proton therapy (IMPT). Materials and methods This study retrospectively analyzed 42 patients with esophageal cancer treated at Shandong Cancer Hospital. The patients were divided into two groups. Twenty-one patients had a 4DCT image with 10 respiratory phases reconstructed (G intra ). In addition, twenty-one patients underwent a second 3D CT scan following the initial one (G inter ). The RayStation11B treatment planning system was used to create the IMPT plans for these two groups of patients. All patients were planned with a prescribed dose of 50.4 Gy (RBE) in 28 fractions for clinical target volume (CTV). 4D dynamic dose (4DDD) was then calculated to assess the interplay effect by considering respiratory motion and dynamic beam delivery for G intra . Seven IMPT plans with different robust optimization parameters were designed for the 21 G inter patient. The setup uncertainties were set to ± 0–6 mm for G inter . Plan quality and dose-volume histogram (DVH) parameters for the target and organs at risk (OARs) were then analyzed. Results For G intra , 4DDD was slightly perturbated compared to the nominal plan dose. The mean value of CTV D 98% of nominal dose and 4DDD were 49.9 and 49.1 Gy (RBE), respectively, and the CTV D 95% were 50.4 and 49.9 Gy (RBE), respectively. For G inter , the DVH parameters of the target area and the OARs showed a linear relationship with the corresponding robust optimization parameters in IMPT. When the robust optimization parameters were set with a larger value, the dose coverage of the target was improved. However, the dose of OARs increased at the same time. The D 98% of the target for the seven plans (setup6, setup5, setup4, setup3, setup2, setup1, setup0 plan) were 49.42 ± 0.75, 48.95 ± 1.21, 48.54 ± 1.48, 47.55 ± 2.31, 47.07 ± 2.71, 44.58 ± 4.20 and 44.02 ± 4.44 Gy(RBE), respectively. The D mean of heart were 12.18 ± 3.05, 11.28 ± 2.86, 10.90 ± 2.77, 9.76 ± 2.39, 9.73 ± 2.39, 8.33 ± 2.22 and 8.22 ± 2.20 Gy (RBE), respectively. Conclusion In this study, the differences in dose distributions between the 4DDD and nominal plans for G intra can be attributed to the interplay effects. While target coverage remained stable, variations in OAR doses should be evaluated for G intra . For G inter , smaller setup uncertainty parameters may not fully mitigate inter-fractional tumor motion, leading to greater variation in target dose and potential inadequate coverage. The linear relationship between setup uncertainty and D 98% suggested that improved setup uncertainties can enhance target coverage, while higher setup uncertainties tend to increase OARs doses, particularly to the heart and lungs.

Purpose To compare dosimetric performance of volumetric‐modulated arc therapy (VMAT) and small‐spot intensity‐modulated proton therapy for stage III non‐small‐cell lung cancer (NSCLC). Methods and Materials A total of 24 NSCLC patients were retrospectively reviewed; 12 patients received intensity‐modulated proton therapy (IMPT) and the remaining 12 received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTV) on averaged 4D‐CTs. The dose‐volume‐histograms (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases of each field per fraction. DVH indices were compared using Wilcoxon rank sum test. Results Compared with VMAT, IMPT delivered significantly lower cord Dmax, heart Dmean, and lung V5 Gy[RBE] with comparable CTV dose homogeneity, and protection of other OARs. In terms of plan robustness, the IMPT plans were statistically better than VMAT plans in heart Dmean, but were statistically worse in CTV dose coverage, cord Dmax, lung Dmean, and V5 Gy[RBE]. Other DVH indices were comparable. The IMPT plans still met the standard clinical requirements with interplay effects considered. Conclusions Small‐spot IMPT improves cord, heart, and lung sparing compared to VMAT and achieves clinically acceptable plan robustness at least for the patients included in this study with motion amplitude less than 11 mm. Our study supports the usage of IMPT to treat some lung cancer patients.

Purpose To compare the dosimetric performances of intensity‐modulated proton therapy (IMPT) plans generated with two different beam angle configurations (the Right–Left oblique posterior beams and the Superior–Inferior oblique posterior beams) for the treatment of distal esophageal carcinoma in the presence of uncertainties and interplay effect. Methods and Materials Twenty patients’ IMPT plans were retrospectively selected, with 10 patients treated with the R‐L oblique posterior beams (Group R‐L) and the other 10 patients treated with the S‐I oblique posterior beams (Group S‐I). Patients in both groups were matched by their clinical target volumes (CTVs—high and low dose levels) and respiratory motion amplitudes. Dose‐volume‐histogram (DVH) indices were used to assess plan quality. DVH bandwidth was calculated to evaluate plan robustness. Interplay effect was quantified using four‐dimensional (4D) dynamic dose calculation with random respiratory starting phase of each fraction. Normal tissue complication probability (NTCP) for heart, liver, and lung was calculated, respectively, to estimate the clinical outcomes. Wilcoxon signed‐rank test was used for statistical comparison between the two groups. Results Compared with plans in Group R‐L, plans in Group S‐I resulted in significantly lower liver Dmean and lung V30Gy[RBE] with slightly higher but clinically acceptable spinal cord Dmax. Similar plan robustness was observed between the two groups. When interplay effect was considered, plans in Group S‐I performed statistically better for heart Dmean and V30Gy[RBE], lung Dmean and V5Gy[RBE], and liver Dmean, with slightly increased but clinically acceptable spinal cord Dmax. NTCP for liver was significantly better in Group S‐I. Conclusions IMPT plans in Group S‐I have better sparing of liver, heart, and lungs at the slight cost of spinal cord maximum dose protection, and are more interplay‐effect resilient compared to IMPT plans in Group R‐L. Our study supports the routine use of the S‐I oblique posterior beams for the treatments of distal esophageal carcinoma.

Purpose Interplay effects may influence dose distributions to a moving target when using dynamic delivery techniques such as intensity‐modulated radiotherapy (IMRT). The aim of this study was to evaluate the impact of organ motion on volumetric and dosimetric parameters in stomach lymphomas treated with IMRT. Methods Ten patients who had been treated with IMRT for stomach lymphomas were enrolled. The clinical target volume (CTV) was contoured as the whole stomach. Considering interfractional uncertainty, the internal target volume (ITV) margin was uniformly 1.5 cm to the CTV and then modified based on the 4DCT images in case of the large respiratory motion. The planning target volume (PTV) was created by adding 5 mm to the ITV. The impact of organ motion on the volumetric and dosimetric parameters was evaluated retrospectively (4D simulation). The organ motion was reproduced by shifting the isocenter on the radiation treatment planning system. Several simulation plans were created to test the influence of the beam‐on timing in the respiration cycle on the dose distribution. The homogeneity index (HI), volume percentage of stomach covered by the prescribed dose (Vp), and D99 of the CTV were evaluated. Results The organ motion was the largest in the superior‐inferior direction (10.1 ± 4.5 mm [average ± SD]). Stomach volume in each respiratory phase compared to the mean volume varied approximately within a ± 5% range in most of the patients. The PTV margin was sufficiently large to cover the CTV during the IMRT. There was a significant reduction in Vp and D99 but not in HI in the 4D simulation in free‐breathing and multiple fractions compared to the clinically‐used plan (P < 0.05) suggesting that interplay effects deteriorate the dose distribution. The absolute difference of D99 was less than 1% of the prescribed dose. Conclusions There were significant interplay effects affecting the dose distribution in stomach IMRT. The magnitude of the dose reduction was small when patients were treated on free‐breathing and multiple fractions.

Background Rescanning is a common technique used in proton pencil beam scanning to mitigate the interplay effect. Advances in machine operating parameters across different generations of particle therapy systems have led to improvements in beam delivery time (BDT). However, the potential impact of these improvements on the effectiveness of rescanning remains an underexplored area in the existing research. Methods We systematically investigated the impact of proton machine operating parameters on the effectiveness of layer rescanning in mitigating interplay effect during lung SBRT treatment, using the CIRS phantom. Focused on the Hitachi synchrotron particle therapy system, we explored machine operating parameters from our institution's current (2015) and upcoming systems (2025A and 2025B). Accumulated dynamic 4D dose were reconstructed to assess the interplay effect and layer rescanning effectiveness. Results Achieving target coverage and dose homogeneity within 2% deviation required 6, 6, and 20 times layer rescanning for the 2015, 2025A, and 2025B machine parameters, respectively. Beyond this point, further increasing the number of layer rescanning did not further improve the dose distribution. BDTs without rescanning were 50.4, 24.4, and 11.4 s for 2015, 2025A, and 2025B, respectively. However, after incorporating proper number of layer rescanning (six for 2015 and 2025A, 20 for 2025B), BDTs increased to 67.0, 39.6, and 42.3 s for 2015, 2025A, and 2025B machine parameters. Our data also demonstrated the potential problem of false negative and false positive if the randomness of the respiratory phase at which the beam is initiated is not considered in the evaluation of interplay effect. Conclusion The effectiveness of layer rescanning for mitigating interplay effect is affected by machine operating parameters. Therefore, past clinical experiences may not be applicable to modern machines.