Dosimetric comparison of IMPT vs VMAT for multiple lung lesions: an NTCP model-based decision-making strategy.

To compare the dosimetric differences in volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) in stereotactic body radiation therapy (SBRT) of multiple lung lesions and determine a normal tissue complication probability (NTCP) model-based decision strategy that determines which treatment modality the patient will use. A total of 41 patients were retrospectively selected for this study. The number of patients with 1-6 lesions was 5, 16, 7, 6, 3, and 4, respectively. A prescription dose of 70 GyRBE in 10 fractions was given to each lesion. SBRT plans were generated using VMAT and IMPT. All the IMPT plans used robustness optimization with ± 3.5% range uncertainties and 5 mm setup uncertainties. Dosimetric metrics and the predicted NTCP value of radiation pneumonitis (RP), esophagitis, and pericarditis were analyzed to evaluate the potential clinical benefits between different planning groups. In addition, a threshold for the ratio of PTV to lungs (%) to determine whether a patient would benefit highly from IMPT was determined using receiver operating characteristic curves. All plans reached target coverage (V70GyRBE ≥ 95%). Compared with VMAT, IMPT resulted in a significantly lower dose of most thoracic normal tissues. For the 1-2, 3-4 and 5-6 lesion groups, the lung V5 was 29.90 ± 9.44%, 58.33 ± 13.35%, and 81.02 ± 5.91% for VMAT and 11.34 ± 3.11% (p < 0.001), 21.45 ± 3.80% (p < 0.001), and 32.48 ± 4.90% (p < 0.001) for IMPT, respectively. The lung V20 was 12.07 ± 4.94%, 25.57 ± 6.54%, and 43.99 ± 11.83% for VMAT and 6.76 ± 1.80% (p < 0.001), 13.14 ± 2.27% (p < 0.01), and 19.62 ± 3.48% (p < 0.01) for IMPT. The Dmean of the total lung was 7.65 ± 2.47 GyRBE, 14.78 ± 2.75 GyRBE, and 21.64 ± 4.07 GyRBE for VMAT and 3.69 ± 1.04 GyRBE (p < 0.001), 7.13 ± 1.41 GyRBE (p < 0.001), and 10.69 ± 1.81 GyRBE (p < 0.001) for IMPT. Additionally, in the VMAT group, the maximum NTCP value of radiation pneumonitis was 73.91%, whereas it was significantly lower in the IMPT group at 10.73%. The accuracy of our NTCP model-based decision model, which combines the number of lesions and PTV/Lungs (%), was 97.6%. The study demonstrated that the IMPT SBRT for multiple lung lesions had satisfactory dosimetry results, even when the number of lesions reached 6. The NTCP model-based decision strategy presented in our study could serve as an effective tool in clinical practice, aiding in the selection of the optimal treatment modality between VMAT and IMPT.

Optimizing linear energy transfer distribution in intensity-modulated proton therapy using the alternating direction method of multipliers.

Purpose: This study develop a novel linear energy transfer (LET) optimization method for intensity-modulated proton therapy (IMPT) with minimum monitor unit (MMU) constraint using the alternating direction method of multipliers (ADMM). Material and methods: The novel LET optimization method (ADMM-LET) was proposed with (1) the dose objective and the LET objective as the optimization objective and (2) the non-convex MMU threshold as a constraint condition. ADMM was used to solve the optimization problem. In the ADMM-LET framework, the optimization process entails iteratively solving the dose sub-problem and the LET sub-problem, simultaneously ensuring compliance with the MMU constraint. Three representative cases, including brain, liver, and prostate cancer, were utilized to evaluate the performance of the proposed method. The dose and LET distributions from ADMM-LET were compared to those obtained using the published iterative convex relaxation (ICR-LET) method. Results: The results demonstrate the superiority of ADMM-LET over ICR-LET in terms of LET distribution while achieving a comparable dose distribution. More specifically, for the brain case, the maximum LET (unit: keV/µm) at the optic nerve decreased from 5.45 (ICR-LET) to 1.97 (ADMM-LET). For the liver case, the mean LET (unit: keV/µm) at the clinical target volume increased from 4.98 (ICR-LET) to 5.50 (ADMM-LET). For the prostate case, the mean LET (unit: keV/µm) at the rectum decreased from 2.65 (ICR-LET) to 2.14 (ADMM-LET). Conclusion: This study establishes ADMM-LET as a new approach for LET optimization with the MMU constraint in IMPT, offering potential improvements in treatment outcomes and biological effects.

Longitudinal Assessment of Quality of Life in Nasopharyngeal Cancer Patients Treated with Intensity-Modulated Proton Therapy and Volumetric Modulated Arc Therapy at Different Time Points.

PURPOSE: This retrospective cohort study aims to compare the quality of life (QoL) in patients with nasopharyngeal cancer (NPC) treated with intensity-modulated proton therapy (IMPT) versus volumetric modulated arc therapy (VMAT) at different time points. MATERIALS AND METHODS: We conducted a longitudinal assessment of QoL on 287 newly diagnosed NPC patients (IMPT: 41 and VMAT: 246). We collected outcomes of global QoL, functional QoL, C30 symptoms, and HN35 symptoms from EORTC QLQ-C30 and QLQ-HN35 questionnaires at pre-radiotherapy, during radiotherapy (around 40 Gy), 3 months post radiotherapy, and 12-months post radiotherapy (RT). The generalized estimating equation was utilized to interpret the group effect, originating from inherent group differences; time effect, attributed to RT effects over time; and interaction of the group and time effect. RESULTS: IMPT demonstrated superior mean dose reductions in 12 of the 16 organs at risk compared to VMAT, including a significant (>50%) reduction in the oral cavity and larynx. Both groups exhibited improved scores of global QoL, functional QoL, and C30 symptoms at 12 months post RT compared to the pre-RT status. Regarding global QoL and C30 symptoms, there was no interaction effect of group over time. In contrast, significant interaction effects were observed on functional QoL (p = 0.040) and HN35 symptoms (p = 0.004) during RT, where IMPT created an average of 7.5 points higher functional QoL and 10.7 points lower HN35 symptoms than VMAT. CONCLUSIONS: Compared to VMAT, dose reduction attributed to IMPT could translate into better functional QoL and HN35 symptoms, but the effect is time dependent and exclusively observed during the RT phase.

A fast and robust constraint-based online re-optimization approach for automated online adaptive intensity modulated proton therapy in head and neck cancer.

Objective. In head-and-neck cancer intensity modulated proton therapy, adaptive radiotherapy is currently restricted to offline re-planning, mitigating the effect of slow changes in patient anatomies. Daily online adaptations can potentially improve dosimetry. Here, a new, fully automated online re-optimization strategy is presented. In a retrospective study, this online re-optimization approach was compared to our trigger-based offline re-planning (offlineTBre-planning) schedule, including extensive robustness analyses.Approach. The online re-optimization method employs automated multi-criterial re-optimization, using robust optimization with 1 mm setup-robustness settings (in contrast to 3 mm for offlineTBre-planning). Hard planning constraints and spot addition are used to enforce adequate target coverage, avoid prohibitively large maximum doses and minimize organ-at-risk doses. For 67 repeat-CTs from 15 patients, fraction doses of the two strategies were compared for the CTVs and organs-at-risk. Per repeat-CT, 10.000 fractions with different setup and range robustness settings were simulated using polynomial chaos expansion for fast and accurate dose calculations.Main results. For 14/67 repeat-CTs, offlineTBre-planning resulted in <50% probability ofD98%≥ 95% of the prescribed dose (Dpres) in one or both CTVs, which never happened with online re-optimization. With offlineTBre-planning, eight repeat-CTs had zero probability of obtainingD98%≥ 95%Dpresfor CTV7000, while the minimum probability with online re-optimization was 81%. Risks of xerostomia and dysphagia grade ≥ II were reduced by 3.5 ± 1.7 and 3.9 ± 2.8 percentage point [mean ± SD] (p< 10-5for both). In online re-optimization, adjustment of spot configuration followed by spot-intensity re-optimization took 3.4 min on average.Significance. The fast online re-optimization strategy always prevented substantial losses of target coverage caused by day-to-day anatomical variations, as opposed to the clinical trigger-based offline re-planning schedule. On top of this, online re-optimization could be performed with smaller setup robustness settings, contributing to improved organs-at-risk sparing.

SISS-MCO: large scale sparsity-induced spot selection for fast and fully-automated robust multi-criteria optimisation of proton plans.

Objective.Intensity modulated proton therapy (IMPT) is an emerging treatment modality for cancer. However, treatment planning for IMPT is labour-intensive and time-consuming. We have developed a novel approach for multi-criteria optimisation (MCO) of robust IMPT plans (SISS-MCO) that is fully automated and fast, and we compare it for head and neck, cervix, and prostate tumours to a previously published method for automated robust MCO (IPBR-MCO, van de Water 2013).Approach.In both auto-planning approaches, the applied automated MCO of spot weights was performed with wish-list driven prioritised optimisation (Breedveld 2012). In SISS-MCO, spot weight MCO was applied once for every patient after sparsity-induced spot selection (SISS) for pre-selection of the most relevant spots from a large input set of candidate spots. IPBR-MCO had several iterations of spot re-sampling, each followed by MCO of the weights of the current spots.Main results.Compared to the published IPBR-MCO, the novel SISS-MCO resulted in similar or slightly superior plan quality. Optimisation times were reduced by a factor of 6 i.e. from 287 to 47 min. Numbers of spots and energy layers in the final plans were similar.Significance.The novel SISS-MCO automatically generated high-quality robust IMPT plans. Compared to a published algorithm for automated robust IMPT planning, optimisation times were reduced on average by a factor of 6. Moreover, SISS-MCO is a large scale approach; this enables optimisation of more complex wish-lists, and novel research opportunities in proton therapy.

Impact of Anatomical Position Errors on Dose Distribution in Head and Neck Radiotherapy and Robust Image Registration Against Anatomical Changes.

BACKGROUND/AIM: This study pursued two goals: Firstly, to search for anatomical structures strongly correlating with dose deterioration, and secondly to investigate the effectiveness of image registration focusing on critical anatomy by comparing it with a conventional method. The aim was to achieve robust image registration to correct for anatomical changes during treatment. PATIENTS AND METHODS: Twenty patients with head and neck cancer were enrolled, and 68 simulation computed tomography (CT) and rescan CT image sets were retrospectively analyzed. Forty volumetric-modulated arc therapy and intensity-modulated proton therapy plans were generated and recalculated according to the rescan CT to evaluate the dose effects of anatomical changes. Correlation coefficients were calculated for the relationships between the six-axis motion of the anatomy and the dose indices for the clinical target volume (CTV) and organs at risk. In the image registration, we compared a conventional method and target-based registration that limited the registration range to the CTV and vertebrae. RESULTS: The CTV coverage and spinal cord dose were correlated with the position error associated with the pitch and vertical position of the vertebrae, and the parotid gland and oral cavity dose were strongly correlated with the position error associated with the roll of the clivus and mandible. The target registration improved CTV coverage and suppressed the increase in dose to organs at risk compared with conventional methods. CONCLUSION: Monitoring vertebral alignment, the assessment and correction of positioning errors associated with the clivus and mandible position errors are important to ensure the quality of daily treatment. Target-based registration may allow for more robust image registration.

Radiation induced lung injury (RILI) after postoperative intensity modulated proton therapy (IMPT) in a patient with stage III locally advanced lung adenocarcinoma: a case report.

Background: Postoperative radiation therapy (PORT) remains the critical therapy for stage III non-small cell lung cancer (NSCLC). Radiation induced lung injury (RILI) is common and affects the clinical outcome. Proton therapy (PT) is a new-style radiotherapy with accurate distribution of curative dose to tumor and increased organ-at-risk (OAR) sparing, which potentially decrease the incidence of RILI. Intensity modulated proton therapy (IMPT) is more flexible and conformal one. Case Description: In the case, we report a 47-year-old man with stage III locally advanced lung adenocarcinoma developing RILI after IMPT. The man had no chronic pulmonary disease before. After 6 cycles every three-week of postoperative adjuvant chemotherapy (pemetrexed, carboplatin), he sequentially received 50 GyE of IMPT in 25 fractions. About 7 weeks after IMPT, grade 2 RILI was developed with the manifestation of focal pulmonary consolidation and ground-glass attenuation. Steroid therapy was delivered and the pneumonias absorbed slightly with chronic scarring and fibrosis left over. Conclusions: RILI after IMPT is not commonplace especially under the circumstance where the patient had no chronic lung disease and the proton dose was conservative. The patient manifested as the early developed acute exudation and fibrosis stage. Moreover, the injury was so refractory that fibrosis was developing in spite of active steroid therapy. Based on the case, we suggested that more exploration of proton induced lung injury and evaluation before IMPT especially following chemotherapy are deserved.

Knowledge-Based Planning for Robustly Optimized Intensity-Modulated Proton Therapy of Head and Neck Cancer Patients.

PURPOSE: To assess the performance of a proton-specific knowledge-based planning (KBP) model in the creation of robustly optimized intensity-modulated proton therapy (IMPT) plans for treatment of advanced head and neck (HN) cancer patients. METHODS: Seventy-three patients diagnosed with advanced HN cancer previously treated with volumetric modulated arc therapy (VMAT) were selected and replanned with robustly optimized IMPT. A proton-specific KBP model, RapidPlanPT (RPP), was generated using 53 patients (20 unilateral cases and 33 bilateral cases). The remaining 20 patients (10 unilateral and 10 bilateral cases) were used for model validation. The model was validated by comparing the target coverage and organ at risk (OAR) sparing in the RPP-generated IMPT plans with those in the expert plans. To account for the robustness of the plan, all uncertainty scenarios were included in the analysis. RESULTS: All the RPP plans generated were clinically acceptable. For unilateral cases, RPP plans had higher CTV_primary V100 (1.59% ± 1.24%) but higher homogeneity index (HI) (0.7 ± 0.73) than had the expert plans. In addition, the RPP plans had better ipsilateral cochlea Dmean (-5.76 ± 6.11 Gy), with marginal to no significant difference between RPP plans and expert plans for all other OAR dosimetric indices. For the bilateral cases, the V100 for all clinical target volumes (CTVs) was higher for the RPP plans than for the expert plans, especially the CTV_primary V100 (5.08% ± 3.02%), with no significant difference in the HI. With respect to OAR sparing, RPP plans had a lower spinal cord Dmax (-5.74 ± 5.72 Gy), lower cochlea Dmean (left, -6.05 ± 4.33 Gy; right, -4.84 ± 4.66 Gy), lower left and right parotid V20Gy (left, -6.45% ± 5.32%; right, -6.92% ± 3.45%), and a lower integral dose (-0.19 ± 0.19 Gy). However, RPP plans increased the Dmax in the body outside of CTV (body-CTV) (1.2 ± 1.43 Gy), indicating a slightly higher hotspot produced by the RPP plans. CONCLUSION: IMPT plans generated by a broad-scope RPP model have a quality that is, at minimum, comparable with, and at times superior to, that of the expert plans. The RPP plans demonstrated a greater robustness for CTV coverage and better sparing for several OARs.

How should we model and evaluate breathing interplay effects in IMPT?

Breathing interplay effects in Intensity Modulated Proton Therapy (IMPT) arise from the interaction between target motion and the scanning beam. Assessing the detrimental effect of interplay and the clinical robustness of several mitigation techniques requires statistical evaluation procedures that take into account the variability of breathing during dose delivery. In this study, we present such a statistical method to model intra-fraction respiratory motion based on breathing signals and assess clinical relevant aspects related to the practical evaluation of interplay in IMPT such as how to model irregular breathing, how small breathing changes affect the final dose distribution, and what is the statistical power (number of different scenarios) required for trustworthy quantification of interplay effects. First, two data-driven methodologies to generate artificial patient-specific breathing signals are compared: a simple sinusoidal model, and a precise probabilistic deep learning model generating very realistic samples of patient breathing. Second, we investigate the highly fluctuating relationship between interplay doses and breathing parameters, showing that small changes in breathing period result in large local variations in the dose. Our results indicate that using a limited number of samples to calculate interplay statistics introduces a bigger error than using simple sinusoidal models based on patient parameters or disregarding breathing hysteresis during the evaluation. We illustrate the power of the presented statistical method by analyzing interplay robustness of 4DCT and Internal Target Volume (ITV) treatment plans for a 8 lung cancer patients, showing that, unlike 4DCT plans, even 33 fraction ITV plans systematically fail to fulfill robustness requirements.

Investigate the Dosimetric and Potential Clinical Benefits Utilizing Stereotactic Body Radiation Therapy With Simultaneous Integrated Boost Technique for Locally Advanced Pancreatic Cancer: A Comparison Between Photon and Proton Beam Therapy.

PURPOSE: To investigate the potential clinical benefits of using stereotactic body radiation therapy (SBRT) with simultaneous integrated boost (SIB) technique for locally advanced pancreatic cancer (LAPC) among different treatment modalities and planning strategies, including photon and proton. METHOD: A total of 19 patients were retrospectively selected in this study: 13 cases with the tumor located in the head of the pancreas and 6 cases with the tumor in the body of the pancreas. SBRT-SIB plans were generated using volumetric modulated arc therapy (VMAT), two-field Intensity Modulated Proton Therapy (IMPT), and three-field IMPT. The IMPT used the robust optimization parameters of ± 3.5% range and 5-mm setup uncertainties. Root-mean-square deviation dose (RMSD) volume histograms were used to evaluate the target coverage robustness quantitatively. Dosimetric metrics based on the dose-volume histogram (DVH), homogeneity index (HI), and normal tissue complication probability (NTCP) were analyzed to evaluate the potential clinical benefits among different planning groups. RESULTS: With a similar CTV and SIB coverage, two-field IMPT provided a lower maximum dose for the stomach (median: 18.6GyE, p<0.05) and duodenum (median: 32.62GyE, p<0.05) when the target was located in the head of the pancreas compared to VMAT and three-field IMPT. The risks of gastric bleed (3.42%) and grade ≥ 3 GI toxicity (4.55%) were also decreased. However, for the target in the body of the pancreas, VMAT showed a lower maximum dose for the stomach (median 30.93GyE, p<0.05) and toxicity of gastric bleed (median: 8.67%, p<0.05) compared to two-field IMPT and three-field IMPT, while other maximum doses and NTCPs were similar. The RMSD volume histogram (RVH) analysis shows that three-field IMPT provided better robustness for targets but not for OARs. Instead, three-field IMPT increased the Dmean of organs such as the stomach, duodenum, and intestine. CONCLUSION: The results indicated that the tumor locations could play a critical role in determining clinical benefits among different treatment modalities. Two-field IMPT could be a better option for LAPC patients whose tumors are located in the head of the pancreas. It provides lower severe toxicity for the stomach and duodenum. Nevertheless, VMAT is preferred for the body with better protection for the possibility of gastric bleed.

Intensity-Modulated Proton Therapy (IMPT) Treatment of Angiosarcoma of the Face and Scalp.

PURPOSE: To successfully plan and treat a patient with diffuse angiosarcoma involving the face and scalp with intensity-modulated proton therapy (IMPT) before surgical resection. MATERIALS AND METHODS: A patient presented to the radiation oncology department for preoperative treatment of an angiosarcoma diffusely involving the face and scalp. A 4-field IMPT technique was used to create a homogeneous dose distribution to the entire target volume while sparing underlying critical structures from toxicity and low-dose spread. A custom Monte Carlo optimizer was necessary to achieve treatment goals. Biological dose was evaluated with a linear energy transfer-based biological enhancement model. Robustness criteria were evaluated per department standard. The patient was successfully planned and treated according to clinical goals. RESULTS: The patient successfully completed the course of IMPT and was able to undergo surgical resection. Pathology indicated no presence of angiosarcoma. CONCLUSION: IMPT using a custom Monte Carlo optimizer is a suitable radiation therapy treatment option for patients with diffuse angiosarcoma of the scalp and face.

Erratum: Investigate the Dosimetric and Potential Clinical Benefits Utilizing Stereotactic Body Radiation Therapy With Simultaneous Integrated Boost Technique for Locally Advanced Pancreatic Cancer: A Comparison Between Photon and Proton Beam Therapy.

[This corrects the article DOI: 10.3389/fonc.2021.747532.].

Pro-con of proton: Dosimetric advantages of intensity-modulation over passive scatter for thoracic malignancies.

The use of passively scattered proton therapy (PSPT) or intensity modulated proton therapy (IMPT) opens the potential for dose escalation or critical structure sparing in thoracic malignancies. While the latter offers greater dose conformality, dose distributions are subjected to greater uncertainties, especially due to interplay effects. Exploration in this area is warranted to determine if there is any dosimetric advantages in using IMPT for thoracic malignancies. This review aims to both compare organs-at-risk sparing and plan robustness between PSPT and IMPT and examine the mitigation strategies for the reduction of interplay effects currently available. Early evidence suggests that IMPT is dosimetrically superior to PSPT in thoracic malignancies. Randomised control trials are required before any clinical benefit of IMPT can be confirmed.

Technical Note: Plan-delivery-time constrained inverse optimization method with minimum-MU-per-energy-layer (MMPEL) for efficient pencil beam scanning proton therapy.

PURPOSE: This work aims to reduce dose delivery time of pencil beam scanning (PBS) proton plans, which is the dominant factor of total plan delivery time. A proton PBS system, such as Varian ProBeam proton therapy system, can be equipped with the proton dose rate that is linearly proportional to the minimum monitor unit (MU) (i.e., number of protons) of PBS spots before saturation. Thus dose delivery time can be potentially reduced by increasing the MU threshold. However, commercially available treatment planning systems and current methods only allow for a single MU threshold globally for all PBS spots (i.e., all energy layers), and consequently the room to increase this minimum-MU for reducing dose delivery time is very limited since higher minimum-MU can greatly degrade treatment plan quality. METHODS: Two major innovations of this work are the proposal of using variable MU thresholds locally adaptive to each energy layer, that is, minimum-MU-per-energy-layer (MMPEL), for reducing dose delivery time, and the joint optimization of plan delivery time and plan quality. Minimum-MU-per-energy-layer is formulated as a constrained optimization problem with objectives of dose-volume-histogram based planning constraints and plan delivery time, and minimum-MU constraints per energy layer for deliverable PBS spots. Minimum-MU-per-energy-layer is solved by iterative convex relaxations via alternating direction method of multipliers. RESULTS: Representative prostate, lung, brain, head-and-neck, breast, liver and pancreas cases were used to validate MMPEL. Minimum-MU-per-energy-layer reduced dose delivery time to 53%, 67%, 67%, 53%, 54%, 32%, and 14% respectively while maintaining a similar plan quality. Accepting a slightly degraded plan quality that still met all physician planning constraints, the treatment time could be further reduced to 26%, 35%, 41%, 34%, 32%, 16%, and 11% respectively, or in another word MMPEL accelerated the PBS plan delivery by 2-10 fold. CONCLUSIONS: A new proton PBS treatment planning method MMPEL with variable energy-adaptive MU thresholds is developed to optimize dose delivery time jointly with plan quality. The preliminary results suggest that MMPEL could substantially reduce dose delivery time.

Managing treatment-related uncertainties in proton beam radiotherapy for gastrointestinal cancers.

In recent years, there has been rapid adaption of proton beam radiotherapy (RT) for treatment of various malignancies in the gastrointestinal (GI) tract, with increasing number of institutions implementing intensity modulated proton therapy (IMPT). We review the progress and existing literature regarding the technical aspects of RT planning for IMPT, and the existing tools that can help with the management of uncertainties which may impact the daily delivery of proton therapy. We provide an in-depth discussion regarding range uncertainties, dose calculations, image guidance requirements, organ and body cavity filling consideration, implanted devices and hardware, use of fiducials, breathing motion evaluations and both active and passive motion management methods, interplay effect, general IMPT treatment planning considerations including robustness plan evaluation and optimization, and finally plan monitoring and adaptation. These advances have improved confidence in delivery of IMPT for patients with GI malignancies under various scenarios.

Technical Note: Integrating an open source Monte Carlo code "MCsquare" for clinical use in intensity-modulated proton therapy.

PURPOSE: To commission an open source Monte Carlo (MC) dose engine, "MCsquare" for a synchrotron-based proton machine, integrate it into our in-house C++-based I/O user interface and our web-based software platform, expand its functionalities, and improve calculation efficiency for intensity-modulated proton therapy (IMPT). METHODS: We commissioned MCsquare using a double Gaussian beam model based on in-air lateral profiles, integrated depth dose of 97 beam energies, and measurements of various spread-out Bragg peaks (SOBPs). Then we integrated MCsquare into our C++-based dose calculation code and web-based second check platform "DOSeCHECK." We validated the commissioned MCsquare based on 12 different patient geometries and compared the dose calculation with a well-benchmarked GPU-accelerated MC (gMC) dose engine. We further improved the MCsquare efficiency by employing the computed tomography (CT) resampling approach. We also expanded its functionality by adding a linear energy transfer (LET)-related model-dependent biological dose calculation. RESULTS: Differences between MCsquare calculations and SOBP measurements were <2.5% (<1.5% for ~85% of measurements) in water. The dose distributions calculated using MCsquare agreed well with the results calculated using gMC in patient geometries. The average 3D gamma analysis (2%/2 mm) passing rates comparing MCsquare and gMC calculations in the 12 patient geometries were 98.0 ± 1.0%. The computation time to calculate one IMPT plan in patients' geometries using an inexpensive CPU workstation (Intel Xeon E5-2680 2.50 GHz) was 2.3 ± 1.8 min after the variable resolution technique was adopted. All calculations except for one craniospinal patient were finished within 3.5 min. CONCLUSIONS: MCsquare was successfully commissioned for a synchrotron-based proton beam therapy delivery system and integrated into our web-based second check platform. After adopting CT resampling and implementing LET model-dependent biological dose calculation capabilities, MCsquare will be sufficiently efficient and powerful to achieve Monte Carlo-based and LET-guided robust optimization in IMPT, which will be done in the future studies.

Plan-library supported automated replanning for online-adaptive intensity-modulated proton therapy of cervical cancer.

Background: Intensity-modulated proton therapy is sensitive to inter-fraction variations, including density changes along the pencil-beam paths and variations in organ-shape and location. Large day-to-day variations are seen for cervical cancer patients. The purpose of this study was to develop and evaluate a novel method for online selection of a plan from a patient-specific library of prior plans for different anatomies, and adapt it for the daily anatomy. Material and methods: The patient-specific library of prior plans accounting for altered target geometries was generated using a pretreatment established target motion model. Each fraction, the best fitting prior plan was selected. This prior plan was adapted using (1) a restoration of spot-positions (Bragg peaks) by adapting the energies to the new water equivalent path lengths; and (2) a spot addition to fully cover the target of the day, followed by a fast optimization of the spot-weights with the reference point method (RPM) to obtain a Pareto-optimal plan for the daily anatomy. Spot addition and spot-weight optimization could be repeated iteratively. The patient cohort consisted of six patients with in total 23 repeat-CT scans, with a prescribed dose of 45 Gy(RBE) to the primary tumor and the nodal CTV. Using a 1-plan-library (one prior plan based on all motion in the motion model) was compared to choosing from a 2-plan-library (two prior plans based on part of the motion). Results: Applying the prior-plan adaptation method with one iteration of adding spots resulted in clinically acceptable target coverage ( V95%≥95% and V107%≤2% ) for 37/46 plans using the 1-plan-library and 41/46 plans for the 2-plan-library. When adding spots twice, the 2-plan-library approach could obtain acceptable coverage for all scans, while the 1-plan-library approach showed V107%>2% for 3/46 plans. Similar OAR results were obtained. Conclusion: The automated prior-plan adaptation method can successfully adapt for the large day-to-day variations observed in cervical cancer patients.

A novel and individualized robust optimization method using normalized dose interval volume constraints (NDIVC) for intensity-modulated proton radiotherapy.

PURPOSE: Intensity-modulated proton therapy (IMPT) is known to be sensitive to patient setup and range uncertainty issues. Multiple robust optimization methods have been developed to mitigate the impact of these uncertainties. Here, we propose a new robust optimization method, which provides an alternative way of robust optimization in IMPT, and is clinically practical, which will enable users to control the balance between nominal plan quality and plan robustness in a user-defined fashion. METHOD: We calculated nine individual dose distributions which corresponded to one nominal and eight extreme scenarios caused by patient setup and proton beam's range uncertainties. For each voxel, the normalized dose interval (NDI) is defined as the full dose range variation divided by the maximum dose in all uncertainty scenarios (NDI = [max - min dose]/max dose), which was then used to calculate the normalized dose interval volume histogram (NDIVH) curves. The areas under the NDIVH curves were used to quantify plan robustness. A normalized dose interval volume constraint (NDIVC) applied to the target was incorporated to specify the desired robustness which was user-defined. Users could then explore the trade-off between nominal plan quality and plan robustness by adjusting the position of the NDIVCs on the NDIVH curves freely. We benchmarked our method using one lung, five head and neck (H&N), and three prostate cases by comparing our results to those derived using the voxel-wise worst-case robust optimization. RESULTS: Using the benchmark cases, our new method achieved quality IMPT plans comparable to those derived from the voxel-wise worst-case robust optimization for both nominal plan quality and plan robustness in general; even more conformal and more homogeneous target dose distributions in some cases, if proper NDIVCs were applied. The AUC under NDIVH, as a precise quantitative index of plan robustness, was consistent with DVH bandwidths. Additionally, we demonstrated the feasibility of adjusting the position of NDIVCs in the NDIVH curves which allowed users to explore the trade-off between nominal plan quality and plan robustness. CONCLUSIONS: The NDIVH-based robust optimization method provided a novel and individualized way of robust optimization in IMPT, and enables users to adjust the balance between nominal plan quality and plan robustness in a user-defined fashion. This method is applicable for continued improvement and developing the next generation of IMPT planning algorithms in the future.

Assessing Novel Drugs and Radiation Technology in the Chemoradiation of Oropharyngeal Cancer.

Integrating immunotherapy, proton therapy and biological dose escalation into the definitive chemoradiation of oropharyngeal cancer poses several challenges. Reliable and reproducible data must be obtained in a timely fashion. However, despite recent international radiotherapy contouring guidelines, controversy persists as to the applicability of such guidelines to all cases. Similarly, a lack of consensus exists concerning both the definition of the organ at risk for oral mucositis and the most appropriate endpoint to measure for this critical toxicity. Finally, the correlation between early markers of efficacy such as complete response on PET CT following treatment and subsequent survival needs elucidation for biological subsets of oropharyngeal cancer.

Proton therapy for thoracic reirradiation of non-small cell lung cancer.

Lung cancer is a leading cause of cancer death with frequent local failures after initial curative-intent treatment. Locally recurrent non-small cell lung cancer represents a challenging clinical scenario as patients have often received prior radiation as part of a definitive treatment regimen. Proton beam therapy, through its characteristic Bragg peak and lack of exit dose is a potential means of minimizing the toxicity to previously irradiated organs and improving the therapeutic ratio. This article aims to review the rationale for the use of proton beam therapy for treatment of locally recurrent non-small cell lung cancer, highlight the current published experience on the feasibility, efficacy, and limitations of proton beam reirradiation, and discuss future avenues for improved patient selection and treatment delivery.