A quantitative framework for patient-specific collision detection in proton therapy.

BACKGROUND: Beam modifying accessories for proton therapy often need to be placed in close proximity of the patient for optimal dosimetry. However, proton treatment units are larger in size and as a result the planned treatment geometry may not be achievable due to collisions with the patient. A framework that can accurately simulate proton treatment geometry is desired. PURPOSE: A quantitative framework was developed to model patient-specific proton treatment geometry, minimize air gap, and avoid collisions. METHODS: The patient's external contour is converted into the International Electrotechnique Commission (IEC) gantry coordinates following the patient's orientation and each beam's gantry and table angles. All snout components are modeled by three-dimensional (3D) geometric shapes such as columns, cuboids, and frustums. Beam-specific parameters such as isocenter coordinates, snout type and extension are used to determine if any point on the external contour protrudes into the various snout components. A 3D graphical user interface is also provided to the planner to visualize the treatment geometry. In case of a collision, the framework's analytic algorithm quantifies the maximum protrusion of the external contour into the snout components. Without a collision, the framework quantifies the minimum distance of the external contour from the snout components and renders a warning if such distance is less than 5 cm. RESULTS: Three different snout designs are modeled. Examples of potential collision and its aversion by snout retraction are demonstrated. Different patient orientations, including a sitting treatment position, as well as treatment plans with multiple isocenters, are successfully modeled in the framework. Finally, the dosimetric advantage of reduced air gap enabled by this framework is demonstrated by comparing plans with standard and reduced air gaps. CONCLUSION: Implementation of this framework reduces incidence of collisions in the treatment room. In addition, it enables the planners to minimize the air gap and achieve better plan dosimetry.

Outcomes and toxicities of definitive radiotherapy and reirradiation using 3-dimensional conformal or intensity-modulated (pencil beam) proton therapy for patients with nasal cavity and paranasal sinus malignancies.

BACKGROUND: Proton therapy (PT) improves outcomes in patients with nasal cavity (NC) and paranasal sinus (PNS) cancers. Herein, the authors have reported to their knowledge the largest series to date using intensity-modulated proton therapy (IMPT) in the treatment of these patients. METHODS: Between 2013 and 2018, a total of 86 consecutive patients (68 of whom were radiation-naive and 18 of whom were reirradiated) received PT to median doses of 70 grays and 67 grays relative biological effectiveness, respectively. Approximately 53% received IMPT. RESULTS: The median follow-up was 23.4 months (range, 1.7-69.3 months) for all patients and 28.1 months (range, 2.3-69.3 months) for surviving patients. The 2-year local control (LC), distant control, disease-free survival, and overall survival rates were 83%, 84%, 74%, and 81%, respectively, for radiation-naive patients and 77%, 80%, 54%, and 66%, respectively for reirradiated patients. Among radiation-naive patients, when compared with 3-dimensional conformal proton technique, IMPT significantly improved LC (91% vs 72%; P < .01) and independently predicted LC (hazard ratio, 0.14; P = .01). Sixteen radiation-naive patients (24%) experienced acute grade 3 toxicities; 4 (6%) experienced late grade 3 toxicities (osteoradionecrosis, vision loss, soft-tissue necrosis, and soft tissue fibrosis) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 5.0]). Slightly inferior LC was noted for patients undergoing reirradiation with higher complications: 11% experienced late grade 3 toxicities (facial pain and brain necrosis). Patients treated with reirradiation had more grade 1 to 2 radionecrosis than radiation-naive patients (brain: 33% vs 7% and osteoradionecrosis: 17% vs 3%). CONCLUSIONS: PT achieved remarkable LC for patients with nasal cavity and paranasal sinus cancers with lower grade 3 toxicities relative to historical reports. IMPT has the potential to improve the therapeutic ratio in these malignancies and is worthy of further investigation.

Early Axial Growth Outcomes of Pediatric Patients Receiving Proton Craniospinal Irradiation.

Guidelines on proton craniospinal irradiation (p-CSI) target volume selection in children are lacking. We examined the impact of target volume selection on growth of children receiving p-CSI at a institution. Records of 58 patients who received p-CSI were reviewed. Median age at treatment initiation was 8 years (range, 2 to 18 y). Spinal target volumes included whole vertebral body (WVB) in 67% and partial vertebral body (PVB) in 33%. Height z-scores before and after p-CSI were assessed using Centers for Disease Control and Prevention stature-for-age charts. Maximal Cobb angle and height z-score change were compared for WVB versus PVB p-CSI using a t test. Among 93% of patients with detailed data, median follow-up was 19 months (range, 2 to 58 mo) after radiation therapy initiation. Quantitative growth evaluations were available for 64% of patients. Median change in height z-score was -0.5 (range, -2.1 to +0.7) after treatment, representing a decrease (P<0.001) in age-adjusted height. WVB patients had significantly greater reduction in height z-score versus PVB patients (P=0.004) but no difference in Cobb angle change (P>0.05). Despite reluctance surrounding its use in younger patients, PVB p-CSI was associated with similar spinal curvature and less growth suppression as compared with WVB p-CSI; a trial comparing WVB versus PVB in children may be warranted.

Contour-based lung dose prediction for breast proton therapy.

PURPOSE: This study evaluates the feasibility of lung dose prediction based on target contour and patient anatomy for breast patients treated with proton therapy. METHODS: Fifty-two randomly selected patients were included in the cohort, who were treated to 50.4-66.4 Gy(RBE) to the left (36), right (15), or bilateral (1) breast with uniform scanning (32) or pencil beam scanning (20). Anterior-oblique beams were used for each patient. The prescription doses were all scaled to 50.4 Gy(RBE) for the current analysis. Isotropic expansions of the planning target volume of various margins m were retrospectively generated and compared with isodose volumes in the ipsilateral lung. The fractional volume V of each expansion contour within the ipsilateral lung was compared with dose-volume data of clinical plans to establish the relationship between the margin m and dose D for the ipsilateral lung such that VD  = V(m). This relationship enables prediction of dose-volume VD from V(m), which could be derived from contours before any plan is generated, providing a goal of plan quality. Lung V20 Gy( RBE ) and V5 Gy( RBE ) were considered for this pilot study, while the results could be generalized to other dose levels and/or other organs. RESULTS: The actual V20 Gy( RBE ) ranged from 6% to 23%. No statistically significant difference in V20 Gy( RBE ) was found between breast irradiation and chest wall irradiation (P = 0.8) or between left-side and right-side treatment (P = 0.9). It was found that V(1.1 cm) predicted V20 Gy( RBE ) to within 5% root-mean-square deviation (RMSD) and V(2.2 cm) predicted V5 Gy( RBE ) to within 6% RMSD. CONCLUSION: A contour-based model was established to predict dose to ipsilateral lung in breast treatment. Clinically relevant accuracy was demonstrated. This model facilitates dose prediction before treatment planning. It could serve as a guide toward realistic clinical goals in the planning stage.

Three-dimensional gamma criterion for patient-specific quality assurance of spot scanning proton beams.

The purpose of this study was to evaluate the effectiveness of full three-dimensional (3D) gamma algorithm for spot scanning proton fields, also referred to as pencil beam scanning (PBS) fields. The difference between the full 3D gamma algorithm and a simplified two-dimensional (2D) version was presented. Both 3D and 2D gamma algorithms are used for dose evaluations of clinical proton PBS fields. The 3D gamma algorithm was implemented in an in-house software program without resorting to 2D interpolations perpendicular to the proton beams at the depths of measurement. Comparison between calculated and measured dose points was car-ried out directly using Euclidian distance in 3D space and the dose difference as a fourth dimension. Note that this 3D algorithm faithfully implemented the original concept proposed by Low et al. (1998) who described gamma criterion using 3D Euclidian distance and dose difference. Patient-specific proton PBS plans are separated into two categories, depending on their optimization method: single-field optimization (SFO) or multifield optimized (MFO). A total of 195 measurements were performed for 58 SFO proton fields. A MFO proton plan with four fields was also calculated and measured, although not used for treatment. Typically three dif-ferent depths were selected from each field for measurements. Each measurement was analyzed by both 3D and 2D gamma algorithms. The resultant 3D and 2D gamma passing rates are then compared and analyzed. Comparison between 3D and 2D gamma passing rates of SFO fields showed that 3D algorithm does show higher passing rates than its 2D counterpart toward the distal end, while little difference is observed at depths away from the distal end. Similar phenomenon in the lateral penumbra was well documented in photon radiation therapy, and in fact brought about the concept of gamma criterion. Although 2D gamma algorithm has been shown to suffice in addressing dose comparisons in lateral penumbra for photon intensity-modulation radiation therapy (IMRT) plans, results here showed that a full 3D algorithm is required for proton dose comparisons due to the existence of Bragg peaks and distal penumbra. A MFO proton plan with four fields was also measured and analyzed. Sharp dose gradients exist in MFO proton fields, both in the middle of the modulation and toward the most distal layers. Decreased 2D gamma passing rates at locations of high dose gradient are again observed as in the SFO fields. Results confirmed that a full 3D algorithm for gamma criterion is needed for proton PBS plan's dose comparisons. The 3D gamma algorithm is implemented by an in-house software program. Patient-specific proton PBS plans are measured and analyzed using both 3D and 2D gamma algorithms. For measurements performed at depths with large dose gradients along the beam direction, gamma comparison passing rates using 2D algorithm is lower than those obtained with the full 3D algorithm.

Evaluation of Proton Therapy Reirradiation for Patients With Recurrent Head and Neck Squamous Cell Carcinoma.

Importance: Use of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret. Objective: To evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma. Design, Setting, and Participants: This retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and grade early and late toxic effects. Exposures: Proton therapy reirradiation. Main Outcomes and Measures: Follow-up was defined from the start of PT-ReRT. The Kaplan-Meier method was used for outcomes of interest, including local control (LC), locoregional control, distant metastatic control, progression-free survival, and overall survival (OS). Cox proportional hazards regression modeling was used to assess associations of covariates with OS. Results: A total of 242 patients (median [range] age, 63 [21-96] years; 183 [75.6%] male) were included. Of these patients, 231 (95.9%) had a Karnofsky performance status score of 70 or higher, and 145 (59.9%) had at least a 10-pack-year smoking history. Median (range) follow-up was 12.0 (5.8-26.0) months for all patients and 24.5 (13.8-37.8) months for living patients. A total of 206 patients (85.1%) had recurrent disease vs second primary or residual disease. The median (range) interval between radiation courses was 22 (1-669) months. Median PT-ReRT dose was 70 cobalt gray equivalents (CGE) for the fractionated cohort and 44.4 CGE for the quad shot cohort. For the fractionated cohort, the 1-year LC was 71.8% (95% CI, 62.8%-79.0%) and the 1-year OS was 66.6% (95% CI, 58.1%-73.8%). For the quad shot cohort, the 1-year LC was 61.6% (95% CI, 46.4%-73.6%) and the 1-year OS was 28.5% (95% CI, 19.4%-38.3%). Higher Karnofsky performance status scores (hazard ratio [HR], 0.50; 95% CI, 0.25-0.99; P = .046) and receipt of salvage surgery prior to PT-ReRT (HR, 0.57; 95% CI, 0.39-0.84; P = .005) were associated with improved OS, whereas receipt of quad shot (HR, 1.97; 95% CI, 1.36-2.86; P < .001) was associated with worse OS. There were a total of 73 grade 3 and 6 grade 4 early toxic effects. There were 79 potential grade 3, 4 grade 4, and 5 grade 5 late toxic effects. Conclusions and Relevance: The findings of this cohort study suggest that, compared with previous reports with photon-based reirradiation, patients are living longer with aggressive PT-ReRT; however, surviving patients remain at risk of early and late complications.

Application of AAPM TG 119 to volumetric arc therapy (VMAT).

The purpose of this study was to create AAPM TG 119 benchmark plans for volumetric arc therapy (VMAT) and to compare VMAT plans with IMRT plan data. AAPM TG 119 proposes a set of test clinical cases for testing the accuracy of IMRT planning and delivery system. For these test cases, we generated two treatment plans, the first plan using 7-9 static dMLC IMRT fields and a second plan utilizing one- or two-arc VMAT technique. Dose optimization and calculations performed using 6 MV photons and Eclipse treatment planning system. Dose prescription and planning objectives were set according to the TG 119 goals. Plans were scored based on TG 119 planning objectives. Treatment plans were compared using conformity index (CI) for reference dose and homogeneity index (HI) (for D(5)-D(95)). For test cases prostate, head-and-neck, C-shape and multitarget prescription dose are 75.6 Gy, 50.4 Gy, 50 Gy and 50 Gy, respectively. VMAT dose distributions were comparable to dMLC IMRT plans. Our planning results matched TG 119 planning results. For treatment plans studied, conformity indices ranged from 1.05-1.23 (IMRT) and 1.04-1.23 (VMAT). Homogeneity indices ranged from 4.6%-11.0% (IMRT) and 4.6%-10.5% (VMAT). The ratio of total monitor units necessary for dMLC IMRT to that of VMAT was in the range of 1.1-2.0. AAPM TG 119 test cases are useful to generate VMAT benchmark plans. At preclinical implementation stage, plan comparison of VMAT and IMRT plans of AAPM TG 119 test case allowed us to understand basic capabilities of VMAT technique.

A Planning Comparison of IMRT vs. Pencil Beam Scanning for Deep Inspiration Breath Hold Lung Cancers.

Deep inspiration breath hold (DIBH) has dosimetric advantages for lung cancer patients treated with external beam therapy, but is difficult for many patients to perform. Proton therapy permits sparing of the downstream organs at risk (OAR). We compared conventionally fractionated proton (p) and photon(x) plans on both free breathing (FB) and DIBH planning CTs to determine the effect of DIBH with proton therapy. We evaluated 24 plans from 6 lung cancer patients treated with photon DIBH on a prospective protocol. All patients were re-planned using pencil beam scanning (PBS) proton therapy. New plans were generated for FB datasets with both modalities. All plans were renormalized to 60 Gy. We evaluated dosimetric parameters for heart, lung and esophagus. We also compared FBp to DIBHx parameters to quantify how FBp plans compare to DIBHx plans. Significant differences were found for lung metrics V20 and mean lung dose between FB and DIBH plans regardless of treatment modality. Furthermore, lung metrics for FBp were comparable or superior to DIBHx, suggesting that FB protons may be a viable alternative for those patients that cannot perform DIBH with IMRT. The heart dose metrics were significantly different for the 5 out of 6 patients where the PTV overlapped the heart as DIBH moved heart out of the high dose volume. Heart dose metrics were further reduced by proton therapy. DIBH offers similar relative advantages for lung sparing for PBS as it does for IMRT but the magnitude of the DIBH related gains in OAR sparing were smaller for PBS than IMRT. FBp plans offer similar or better lung and heart sparing compared to DIBHx plans. For IMRT patients who have difficulty performing DIBH, FB protons may offer an alternative.

Determination of action thresholds for electromagnetic tracking system-guided hypofractionated prostate radiotherapy using volumetric modulated arc therapy.

PURPOSE: Hypofractionated prostate radiotherapy may benefit from both volumetric modulated are therapy (VMAT) due to shortened treatment time and intrafraction real-time monitoring provided by implanted radiofrequency(RF) transponders. The authors investigate dosimetrically driven action thresholds (whether treatment needs to be interrupted and patient repositioned) in VMAT treatment with electromagnetic (EM) tracking. METHODS: VMAT plans for five patients are generated for prescription doses of 32.5 and 42.5 Gy in five fractions. Planning target volume (PTV) encloses the clinical target volume (CTV) with a 3 mm margin at the prostate-rectal interface and 5 mm elsewhere. The VMAT delivery is modeled using 180 equi-spaced static beams. Intrafraction prostate motion is simulated in the plan by displacing the beam isocenter at each beam assuming rigid organ motion according to a previously recorded trajectory of the transponder centroid. The cumulative dose delivered in each fraction is summed over all beams. Two sets of 57 prostate motion trajectories were randomly selected to form a learning and a testing dataset. Dosimetric end points including CTV D95%, rectum wall D1cc, bladder wall D1cc, and urethra Dmax, are analyzed against motion characteristics including the maximum amplitude of the anterior-posterior (AP), superior-inferior (SI), and left-right components. Action thresholds are triggered when intrafraction motion causes any violations of dose constraints to target and organs at risk (OAR), so that treatment is interrupted and patient is repositioned. RESULTS: Intrafraction motion has a little effect on CTV D95%, indicating PTV margins are adequate. Tight posterior and inferior action thresholds around 1 mm need to be set in a patient specific manner to spare organs at risk, especially when the prescription dose is 42.5 Gy. Advantages of setting patient specific action thresholds are to reduce false positive alarms by 25% when prescription dose is low, and increase the sensitivity of detecting dose limits violations by 30% when prescription dose is high, compared to a generic 2 mm action box. The sensitivity and specificity calculated from the testing dataset are consistent to the learning set, which indicates that the patient specific approach is reliable and reproducible within the scope of the prostate database. CONCLUSIONS: This work introduces a formalism for ensuring a VMAT delivery meets the most clinically important dose requirements by using patient specific and dosimetric-driven action thresholds to hold the beam and reposition the patient when necessary. Such methods can provide improved sensitivity and specificity compared to conventional methods, which assume directionally symmetric action thresholds.

Experience of micromultileaf collimator linear accelerator based single fraction stereotactic radiosurgery: tumor dose inhomogeneity, conformity, and dose fall off.

PURPOSE: Sharp dose fall off outside a tumor is essential for high dose single fraction stereotactic radiosurgery (SRS) plans. This study explores the relationship among tumor dose inhomogeneity, conformity, and dose fall off in normal tissues for micromultileaf collimator (mMLC) linear accelerator (LINAC) based cranial SRS plans. METHODS: Between January 2007 and July 2009, 65 patients with single cranial lesions were treated with LINAC-based SRS. Among them, tumors had maximum diameters < or = 20 mm: 31; between 20 and 30 mm: 21; and > 30 mm: 13. All patients were treated with 6 MV photons on a Trilogy linear accelerator (Varian Medical Systems, Palo Alto, CA) with a tertiary m3 high-resolution mMLC (Brainlab, Feldkirchen, Germany), using either noncoplanar conformal fixed fields or dynamic conformal arcs. The authors also created retrospective study plans with identical beam arrangement as the treated plan but with different tumor dose inhomogeneity by varying the beam margins around the planning target volume (PTV). All retrospective study plans were normalized so that the minimum PTV dose was the prescription dose (PD). Isocenter dose, mean PTV dose, RTOG conformity index (CI), RTOG homogeneity index (HI), dose gradient index R50-R100 (defined as the difference between equivalent sphere radius of 50% isodose volume and prescription isodose volume), and normal tissue volume (as a ratio to PTV volume) receiving 50% prescription dose (NTV50) were calculated. RESULTS: HI was inversely related to the beam margins around the PTV. CI had a "V" shaped relationship with HI, reaching a minimum when HI was approximately 1.3. Isocenter dose and mean PTV dose (as percentage of PD) increased linearly with HI. R50-R100 and NTV50 initially declined with HI and then reached a plateau when HI was approximately 1.3. These trends also held when tumors were grouped according to their maximum diameters. The smallest tumor group (maximum diameters < or = 20 mm) had the most HI dependence for dose fall off. For treated plans, CI averaged 2.55 +/- 0.79 with HI 1.23 +/- 0.06; the average R50-R100 was 0.41 +/- 0.08, 0.55 +/- 0.10, and 0.65 +/- 0.09 cm, respectively, for tumors < or = 20 mm, between 20 and 30 mm, and > 30 mm. CONCLUSIONS: Tumor dose inhomogeneity can be used as an important and convenient parameter to evaluate mMLC LINAC-based SRS plans. Sharp dose fall off in the normal tissue is achieved with sufficiently high tumor dose inhomogeneity. By adjusting beam margins, a homogeneity index of approximately 1.3 would provide best conformity for the authors' SRS system.

Multi-scale regularization approaches of non-parametric deformable registrations.

Most deformation algorithms use a single-value smoother during optimization. We investigate multi-scale regularizations (smoothers) during the multi-resolution iteration of two non-parametric deformable registrations (demons and diffeomorphic algorithms) and compare them to a conventional single-value smoother. Our results show that as smoothers increase, their convergence rate decreases; however, smaller smoothers also have a large negative value of the Jacobian determinant suggesting that the one-to-one mapping has been lost; i.e., image morphology is not preserved. A better one-to-one mapping of the multi-scale scheme has also been established by the residual vector field measures. In the demons method, the multi-scale smoother calculates faster than the large single-value smoother (Gaussian kernel width larger than 0.5) and is equivalent to the smallest single-value smoother (Gaussian kernel width equals to 0.5 in this study). For the diffeomorphic algorithm, since our multi-scale smoothers were implemented at the deformation field and the update field, calculation times are longer. For the deformed images in this study, the similarity measured by mean square error, normal correlation, and visual comparisons show that the multi-scale implementation has better results than large single-value smoothers, and better or equivalent for smallest single-value smoother. Between the two deformable registrations, diffeormophic method constructs better coherence space of the deformation field while the deformation is large between images.

Proton reirradiation for recurrent or new primary breast cancer in the setting of prior breast irradiation.

BACKGROUND AND PURPOSE: Late local recurrences and second primary breast cancers are increasingly common. Proton beam therapy (PBT) reirradiation (reRT) may allow safer delivery of a second definitive radiotherapy (RT) course. We analyzed outcomes of patients with recurrent or new primary breast cancer who underwent reRT. MATERIALS AND METHODS: In an IRB-approved retrospective study, patient/tumor characteristics, treatment parameters, outcomes, and toxicities were collected for all consecutive patients with recurrent or new primary non-metastatic breast cancer previously treated with breast or chest wall RT who underwent PBT reRT. RESULTS: Forty-six patients received reRT using uniform (70%) or pencil beam (30%) scanning PBT. Median first RT, reRT, and cumulative doses were 60 Gy (range 45-66 Gy), 50.4 Gy(RBE) (40-66.6 Gy(RBE)), and 110 Gy(RBE) (96.6-169.4 Gy(RBE)), respectively. Median follow-up was 21 months. There were no local or regional recurrences; 17% developed distant recurrence. Two-year DMFS and OS were 92.0% and 93.6%, respectively. Nine of 13 (69.2%) patients who underwent implant or flap reconstruction developed capsular contracture, 3 (23.1%) requiring surgical intervention. One (7.7%) patient developed grade 3 breast pain requiring mastectomy after breast conserving surgery. No acute or late grade 4-5 toxicities were seen. Increased body mass index (BMI) was protective of grade ≥ 2 acute toxicity (OR = 0.84, 95%CI = 0.70-1.00). CONCLUSION: In the largest series to date of PBT reRT for breast cancer recurrence or new primary after prior definitive breast or chest wall RT, excellent locoregional control and few high-grade toxicities were encountered. PBT reRT may provide a relatively safe and highly effective salvage option. Additional patients and follow-up are needed to correlate composite normal tissue doses with toxicities and assess long-term outcomes.

Toxicity Profiles and Survival Outcomes Among Patients With Nonmetastatic Nasopharyngeal Carcinoma Treated With Intensity-Modulated Proton Therapy vs Intensity-Modulated Radiation Therapy.

Importance: Patients with nonmetastatic nasopharyngeal carcinoma (NPC) are primarily treated by radiotherapy with curative intent with or without chemotherapy and often experience substantial treatment-related toxic effects even with modern radiation techniques, such as intensity-modulated radiation therapy (IMRT). Intensity-modulated proton therapy (IMPT) may improve the toxicity profile; however, there is a paucity of data given the limited availability of IMPT in regions with endemic NPC. Objective: To compare toxic effects and oncologic outcomes among patients with newly diagnosed nonmetastatic NPC when treated with IMPT vs IMRT with or without chemotherapy. Design, Setting, and Participants: This retrospective cohort study included 77 patients with newly diagnosed nonmetastatic NPC who received curative-intent radiotherapy with IMPT or IMRT at a tertiary academic cancer center from January 1, 2016, to December 31, 2019. Forty-eight patients with Epstein-Barr virus (EBV)-positive tumors were included in a 1:1 propensity score-matched analysis for survival outcomes. The end of the follow-up period was March 31, 2021. Exposures: IMPT vs IMRT with or without chemotherapy. Main Outcomes and Measures: The main outcomes were the incidence of acute and chronic treatment-related adverse events (AEs) and oncologic outcomes, including locoregional failure-free survival (LRFS), progression-free survival (PFS), and overall survival (OS). Results: We identified 77 patients (25 [32.5%] women; 52 [67.5%] men; median [interquartile range] age, 48.7 [42.2-60.3] years), among whom 28 (36.4%) were treated with IMPT and 49 (63.6%) were treated with IMRT. Median (interquartile range) follow-up was 30.3 (17.9-41.5) months. On multivariable logistic regression analyses, IMPT was associated with lower likelihood of developing grade 2 or higher acute AEs compared with IMRT (odds ratio [OR], 0.15; 95% CI, 0.03-0.60; P = .01). Only 1 case (3.8%) of a chronic grade 3 or higher AE occurred in the IMPT group compared with 8 cases (16.3%) in the IMRT group (OR, 0.21; 95% CI, 0.01-1.21; P = .15). Propensity score matching generated a balanced cohort of 48 patients (24 IMPT vs 24 IMRT) and found similar PFS in the IMPT and IMRT groups (2-year PFS, 95.7% [95% CI, 87.7%-100%] vs 76.7% [95% CI, 60.7%-97.0%]; hazard ratio [HR], 0.31; 95% CI, 0.07-1.47; P = .14). No locoregional recurrence or death was observed in the IMPT group from the matched cohort. Two-year LRFS was 100% (95% CI, 100%-100%) in the IMPT group and 86.2% (95% CI, 72.8%-100%) in the IMRT group (P = .08). Three-year OS was 100% (95% CI, 100%-100%) in the IMPT group and 94.1% (95% CI, 83.6%-100%) in the IMRT group (P = .42). Smoking history was the only clinical factor significantly associated with both poor LRFS (HR, 63.37; 95% CI, 3.25-1236.13; P = .006) and poor PFS (HR, 6.33; 95% CI, 1.16-34.57; P = .03) on multivariable analyses. Conclusions and Relevance: In this study, curative-intent radiotherapy with IMPT for nonmetastatic NPC was associated with significantly reduced acute toxicity burden in comparison with IMRT, with rare late complications and excellent oncologic outcomes, including 100% locoregional control at 2 years. Prospective trials are warranted to direct the optimal patient selection for IMPT as the primary radiotherapy modality for nonmetastatic NPC.

Retrospective analysis of reduced energy switching and room switching times on throughput efficiency of a multi-room proton therapy center.

OBJECTIVE: To quantify how a control software upgrade changed beam delivery times and impacted efficiency and capacity of a multiroom proton therapy center. METHODS: A four-room center treating approximately 90 patients/day, treating for approximately 7 years with optimized operations, underwent a software upgrade which reduced room and energy switching times from approximately 30 to 20 s and approximately 4 s to ~0.5 s, respectively. The center uses radio-frequency identification data to track patient treatments and has software which links this to beam delivery data extracted from the treatment log server. Two 4-month periods, with comparable patient volume, representing periods before and after the software change, were retrospectively analyzed. RESULTS: A total of 16,168 and 17,102 fields were analyzed. For bilateral head and neck and prostate patients, the beam waiting time was reduced by nearly a factor of 3 and the beam delivery times were reduced by nearly a factor of 2.5. Room switching times were reduced more modestly. Gantry capacity has increased from approximately 30 patients to 40-45 patients in a 16-h daily operation. CONCLUSIONS: Many proton centers are striving for increased efficiencies. We demonstrated that reductions in energy and room switching time can significantly increase center capacity. Greater potential for further gains would come from improvements in setup and imaging efficiency. ADVANCES IN KNOWLEDGE: This paper provides detailed measured data on the effect on treatment times resulting from reducing energy and room switching times under controlled conditions. It helps validate the models of previous investigations to establish treatment capacity of a proton therapy center.

Dosimetric evaluation of MR-derived synthetic-CTs for MR-only proton treatment planning.

PURPOSE: To evaluate proton dose calculation accuracy of optimized pencil beam scanning (PBS) plans on MR-derived synthetic-CTs for prostate patients. MATERIAL AND METHODS: Ten patient datasets with both a CT and an MRI were planned with opposed lateral proton beams optimized to single field uniform dose under an IRB-approved study. The proton plans were created on CT datasets generated by a commercial synthetic CT-based software called MRCAT (MR for Calculating ATtenuation) routinely used in our clinic for photon-based MR-only planning. A standard prescription of 79.2 Gy (RBE) and 68.4 Gy (RBE) was used for intact prostate and prostate bed cases, respectively. Proton plans were first generated and optimized using the MRCAT synthetic-CT (syn-CT), and then recalculated on the planning CT rigidly aligned with the syn-CT (aligned-CT) and a deformed planning CT (deformed-CT), which was deformed to match outer contour between syn-CT and aligned-CT. The same beam arrangement, total MUs, MUs/spot, spot positions were used to recalculate dose on deformed-CT and aligned-CT without renormalization. DVH analysis was performed on aligned-CT, deformed-CT, and syn-CT to compare D98%, V100%, V95% for PTV, PTVeval, and GTV as well as V70Gy, V50Gy for OARs. RESULTS: The relative percentage dose difference between syn-CT and deformed-CT, were (0.17 ± 0.33 %) for PTVeval D98% and (0.07 ± 0.1 %) for CTV D98%. Rectum V70Gy, V50Gy, and Bladder V70Gy were (2.76 ± 4.01 %), (11.6 ± 11.2 %), and (3.41 ± 2.86 %), respectively for the syn-CT, and (3.23 ± 3.63 %), (11.3 ± 8.18 %), and (3.29 ± 2.76 %), respectively for the deformed-CT, and (1.37 ± 1.84 %), (8.48 ± 6.67 %), and (4.91 ± 3.65 %), respectively for aligned-CT. CONCLUSION: Dosimetric analysis shows that MR-only proton planning is feasible using syn-CT based on current clinical margins that account for a range uncertainty.

Temporal Lobe Necrosis in Head and Neck Cancer Patients after Proton Therapy to the Skull Base.

PURPOSE: To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base. MATERIALS AND METHODS: Medical records and dosimetric data for radiation-naïve patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with <3 months of follow-up, receiving <45 GyRBE or nonconventional fractionation, and/or no follow-up magnetic resonance imaging (MRI) were excluded. TLN was determined using MRI and graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Clinical (gender, age, comorbidities, concurrent chemotherapy, smoking, radiation techniques) and dose-volume parameters were analyzed for TLN correlation. The receiver operating characteristic curve and area under the curve (AUC) were performed to determine the cutoff points of significant dose-volume parameters. RESULTS: Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range = 3.2-69.3). Overall TLN rates of any grade, ≥ grade 2, and ≥ grade 3 were 5.6% (N = 13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporal lobe; and dose to the 0.5, 1, and 2 cm3 volume receiving the maximum dose (D0.5cm3, D1cm3, and D2cm3, respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm3 gave the highest AUC (0.935) among dose parameters. The 11-cm3 cutoff value for aV50 and 62 GyRBE for D2cm3 showed maximum specificity and sensitivity. CONCLUSION: The estimated 2-year TLN rate was 4.6% with a low rate of toxicities ≥grade 3; aV50 ≤11 cm3, D2cm3 ≤62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.

Early outcomes of breast cancer patients treated with post-mastectomy uniform scanning proton therapy.

BACKGROUND: Postmastectomy proton radiotherapy improves normal tissue sparing in comparison to photon-based approaches. Several studies have reported dosimetry comparison and tolerable acute toxicity profile with limited follow-up. We report our institutional experience of postmastectomy proton radiation including clinical efficacy and toxicities. METHODS: From December 2013 to February 2015, 42 consecutive patients who received mastectomy for non-metastatic breast cancer were treated with adjuvant chest wall and regional nodal proton therapy at a single proton center. 3D conformal uniform scanning with en face matching fields was used. RESULTS: The median follow-up among patients was 35 months (range 1-55 months). There was one local failure, zero regional nodal failure, and six distant failures. The 3-year rate of locoregional disease-free survival was 96.3%, metastasis-free survival was 84.1%, and overall survival was 97.2%. The only local failure event occurred on the chest wall within the radiation field, approximately 2.5 years after the completion of radiation. Skin dermatitis, fatigue, and esophagitis were the most common acute toxicity. All patients developed grade 1 or 2 acute skin toxicity and there was no grade 3 or 4 acute skin toxicity. Proton radiation is able to achieve excellent target coverage with median PTV V95 over 95% and heart sparing with median mean heart dose less than 1 Gy (RBE). CONCLUSION: With close to three years of median follow-up, post-mastectomy proton radiation has shown excellent locoregional control rates and favorable toxicity profile. Long-term adverse effect of heart-sparing radiation will require longer follow-up time and randomized clinical trials.

Organ preservation for patients with anterior mucosal squamous cell carcinoma of the nasal cavity: Rhinectomy-free survival in those refusing surgery.

BACKGROUND: Standard treatment of squamous cell carcinoma (SCC) of the anterior nasal mucosa is surgical resection with or without postoperative radiation. METHODS: Retrospective review of patients diagnosed with SCC of the nasal cavity between January 2000 and July 2018 who refused total rhinectomy and who were treated with radiation with or without chemotherapy with curative intent. RESULTS: Eleven patients were identified, 73% had stage III or stage IV disease. Four patients were treated with intensity-modulated radiotherapy and seven with intensity-modulated proton radiotherapy. Concurrent chemoradiotherapy was used in nine patients (82%). With a median follow-up of 15 months (3-124 months), two patients experienced recurrence and one developed distant metastasis and died from disease. The 2-year rhinectomy-free survival rate was 88%. Two-year overall survival and recurrence-free survival were 100% and 75%, respectively. CONCLUSION: A radiation-based approach for SCC of the nasal cavity mucosa is a valid option for selected patients who refuse up-front surgery.

Image guidance in radiation oncology treatment planning: the role of imaging technologies on the planning process.

Radiation therapy has evolved from 2-dimensional (2D) to 3-dimensional (3D) treatments and, more recently, to intensity-modulated radiation therapy and image-guided radiation therapy. Improvements in imaging have enabled improvements in targeting and treatment. As computer-processing power has improved during the past few decades, it has facilitated developments in both imaging and treatment. The historical role of imaging from 2D to image-guided radiation therapy is reviewed here. Examples of imaging technologies such as positron emission tomography and magnetic resonance imaging are provided. The role of these imaging technologies, organ motion management approaches and their potential impacts on radiation therapy are described.

ICRU reference dose in an era of intensity-modulated radiation therapy clinical trials: correlation with planning target volume mean dose and suitability for intensity-modulated radiation therapy dose prescription.

BACKGROUND AND PURPOSE: IMRT clinical trials lack dose prescription and specification standards similar to ICRU standards for two- and three-dimensional external beam planning. In this study, we analyzed dose distributions for patients whose treatment plans incorporated IMRT, and compared the dose determined at the ICRU reference point to the PTV doses determined from dose-volume histograms. Additionally, we evaluated if ICRU reference type single-point dose prescriptions are suitable for IMRT dose prescriptions. MATERIALS AND METHODS: For this study, IMRT plans of 117 patients treated at our institution were randomly selected and analyzed. The treatment plans were clinically applied to the following disease sites: abdominal (11), anal (10), brain (11), gynecological (15), head and neck (25), lung (15), male pelvis (10) and prostate (20). The ICRU reference point was located in each treatment plan following ICRU Report 50 guidelines. The reference point was placed in the central part of the PTV and at or near the isocenter. In each case, the dose was calculated and recorded to this point. For each patient--volume and dose (PTV, PTV mean, median and modal) information was extracted from the planned dose-volume histogram. RESULTS: The ICRU reference dose vs PTV mean dose relationship in IMRT exhibited a weak positive association (Pearson correlation coefficient 0.63). In approximately 65% of the cases studied, dose at the ICRU reference point was greater than the corresponding PTV mean dose. The dose difference between ICRU reference and PTV mean doses was 2% in approximately 79% of the cases studied (average 1.21% (+/-1.55), range -4% to +4%). Paired t-test analyses showed that the ICRU reference doses and PTV median doses were statistically similar (p=0.42). The magnitude of PTV did not influence the difference between ICRU reference and PTV mean doses. CONCLUSIONS: The general relationship between ICRU reference and PTV mean doses in IMRT is similar to that in 3D CRT distributions. Point doses in IMRT are influenced by the degree of intensity modulation as well as calculation grid size utilized. Although the ICRU reference point type prescriptions conceptually may be extended for IMRT dose prescriptions and used as a representative of tumor dose, new universally acceptable dose prescription and specification standards for IMRT based on RTOG IMRT prescription model incorporating dose-volume specification would likely lead to greater consistency among treatment centers.