Anatomic change over the course of treatment for non-small cell lung cancer patients and its impact on intensity-modulated radiation therapy and passive-scattering proton therapy deliveries.

PURPOSE: To quantify tumor anatomic change of non-small cell lung cancer (NSCLC) patients given passive-scattering proton therapy (PSPT) and intensity-modulated radiation therapy (IMRT) through 6-7 weeks of treatment, and analyze the correlation between anatomic change and the need to adopt adaptive radiotherapy (ART). MATERIALS AND METHODS: Weekly 4D CT sets of 32 patients (8/8 IMRT with/without ART, 8/8 PSPT with/without ART) acquired during treatment, were registered to the planning CT using an in-house developed deformable registration algorithm. The anatomic change was quantified as the mean variation of the region of interest (ROI) relative to the planning CT by averaging the magnitude of deformation vectors of all voxels within the ROI contour. Mean variations of GTV and CTV were compared between subgroups classified by ART status and treatment modality using the independent t-test. Logistic regression analysis was performed to clarify the effect of anatomic change on the probability of ART adoption. RESULTS: There was no significant difference (p = 0.679) for the time-averaged mean CTV variations from the planning CT between IMRT (7.61 ± 2.80 mm) and PSPT (7.21 ± 2.67 mm) patients. However, a significant difference (p = 0.001) was observed between ART (8.93 ± 2.19 mm) and non-ART (5.90 ± 2.33 mm) patients, when treatment modality was not considered. Mean CTV variation from the planning CT in all patients increases significantly (p < 0.001), with a changing rate of 1.77 mm per week. Findings for the GTV change was similar. The logistic regression model correctly predicted 71.9% of cases in ART adoption. The correlation is stronger in the PSPT group with a pseudo R2 value of 0.782, compared to that in the IMRT group (pseudo R2 = 0.182). CONCLUSION: The magnitude of target volume variation over time could be greater than the usual treatment margin. Mean target volume variation from the planning position can be used to identify lung cancer patients that may need ART.

An analytical model for the upper bound estimation of respiratory motion-induced dose uncertainty in spot-scanning proton beam therapy.

PURPOSE: We developed an analytical model of a spot-scanning beam delivery system to estimate the upper bound of respiratory motion-induced dose uncertainty for a given treatment plan. METHODS: The effective delivery time for each spot position in the treatment plan was calculated on the basis of the parameters of the delivery system. The upper bound of the dose uncertainty was then calculated as a function of the effective delivery time. Two-dimensional (2D) measurements with a detector array on a one-dimensional moving platform were obtained to validate the model. RESULTS: We performed 351 two-dimensional measurements on a moving platform for different delivery sequences of a single-layer uniform pattern and patient treatment field. The measured dose uncertainty was a strong function of the effective delivery time: The shortest effective delivery time resulted in a maximum absolute dose error of >90%, while the longest ones resulted in a maximum absolute dose error of 4.9% for a single layer and 9.7% for a patient field with heterogeneity. The relationship of the effective delivery time and the measured dose uncertainty followed the analytical formula. CONCLUSIONS: With our analytical model, the upper bound of the dose uncertainty due to motion can be estimated in spot-scanning proton therapy without four-dimensional dynamic dose calculation.

Power-law relationship in the long-tailed sections of proton dose distributions.

The halo portion of a proton therapy dose creates a long tail in proton dose distributions, but so far study of this phenomenon has been limited. We used statistical methods and mathematical models to confirm that the long-tailed portion of proton dose distributions exhibits a power-law relationship. By analyzing 299 measured dose profiles, we found that all proton lateral dose distributions had a significant power-law scaling correlation with a high correlation coefficient in the tail. We set up a dual-mechanism model, containing both direct and indirect impact mechanisms. In the direct impact mechanism, the proximal dose deposition is mainly due to the direct impact of a proton on a particle. In the indirect mechanism, the impact of a proton on a given particle is considered in terms of the proton's impact on a neighboring particle that then impacts the given particle. We found that the indirect impact mechanism led to a tail in the distribution exhibiting a power-law relationship because the probability of the indirect impacts was proportional to the distance; i.e., the longer the distance, the larger the indirect impact probability. Upon analyzing the experimental data, we observed that the power-law exponent increased with proton energy.

Proton Beam Radiotherapy and Concurrent Chemotherapy for Unresectable Stage III Non-Small Cell Lung Cancer: Final Results of a Phase 2 Study.

Importance: Proton beam radiotherapy (PBT) has the potential to reduce toxic effects in the definitive management of locally advanced non-small cell lung cancer (NSCLC), but long-term prospective data are lacking. Objective: To report the final (5-year) results of a prospective study evaluating concurrent chemotherapy and high-dose PBT to treat unresectable stage III NSCLC. Design, Setting, and Participants: In this open-label, single-group assignment study, with median follow-up of 27.3 months for all patients and 79.6 months for survivors, 64 patients were enrolled and analyzed; inclusion criteria were unresectable IIIA/IIIB histologically confirmed NSCLC, Karnofsky performance status 70 to 100, and 6-month prediagnosis weight loss of no more than 10%. Staging used positron emission tomography and/or computed tomography. Induction chemotherapy was allowed. Interventions: Concurrent chemotherapy (carboplatin-paclitaxel) and passively scattered PBT (74-Gy relative biological effectiveness) in all patients. Main Outcomes and Measures: Kaplan-Meier analysis of overall survival (OS), progression-free survival (PFS), actuarial distant metastasis, and locoregional recurrence. Patterns of treatment failure were categorized as local/regional or distant. Acute and late toxic effects were prospectively assigned using Common Terminology Criteria for Adverse Events, v3.0. Results: Of 64 patients (22 [34%] female; median [range] age, 70 [37-78] years; stage IIIA, 30 [47%]; IIIB, 34 [53%]), 17 (27%) were alive at last follow-up. Median OS was 26.5 months (5-year OS, 29%; 95% CI, 18%-41%). Five-year PFS was 22% (95% CI, 12%-32%); 5-year actuarial distant metastasis and locoregional recurrence were 54% (n = 36) and 28% (n = 22), respectively. Treatment failures were largely (31 [48%] patients) distant, with low rates of crude local (10 [16%]) and regional (9 [14%]) recurrences. Rates of grade 2 and 3 acute esophagitis were 18 (28%) and 5 (8%), respectively. Acute grade 2 pneumonitis occurred in 1 (2%) patient. Late toxic effects were uncommon: 1 (2%) patient developed an esophageal stricture (grade 2) and 1 (2%) grade 4 esophagitis. Late grades 2 and 3 pneumonitis occurred in 10 (16%) and 8 (12%), respectively. Two (3%) patients developed a bronchial stricture (grade 2), and 1 (2%) a grade 4 bronchial fistula. There were no acute or late grade 5 toxic effects. Conclusions and Relevance: Concurrent chemotherapy and PBT to treat unresectable NSCLC afford promising clinical outcomes and rates of toxic effects compared with historical photon therapy data. Further optimization of proton therapy, particularly intensity-modulated proton therapy, is still needed.

Spot scanning proton therapy minimizes neutron dose in the setting of radiation therapy administered during pregnancy.

This is a real case study to minimize the neutron dose equivalent (H) to a fetus using spot scanning proton beams with favorable beam energies and angles. Minimum neutron dose exposure to the fetus was achieved with iterative planning under the guidance of neutron H measurement. Two highly conformal treatment plans, each with three spot scanning beams, were planned to treat a 25-year-old pregnant female with aggressive recurrent chordoma of the base of skull who elected not to proceed with termination. Each plan was scheduled for delivery every other day for robust target coverage. Neutron H to the fetus was measured using a REM500 neutron survey meter placed at the fetus position of a patient simulating phantom. 4.1 and 44.1 µSv/fraction were measured for the two initial plans. A vertex beam with higher energy and the fetal position closer to its central axis was the cause for the plan that produced an order higher neutron H. Replacing the vertex beam with a lateral beam reduced neutron H to be comparable with the other plan. For a prescription of 70 Gy in 35 fractions, the total neutron H to the fetus was estimated to be 0.35 mSv based on final measurement in single fraction. In comparison, the passive scattering proton plan and photon plan had an estimation of 26 and 70 mSv, respectively, for this case. While radiation therapy in pregnant patients should be avoided if at all possible, our work demonstrated spot scanning beam limited the total neutron H to the fetus an order lower than the suggested 5 mSv regulation threshold. It is far superior than passive scattering beam and careful beam selection with lower energy and keeping fetus further away from beam axis are essential in minimizing the fetus neutron exposure.

Novel Hybrid Scattering- and Scanning-Beam Proton Therapy Approach.

PURPOSE: To determine whether a hybrid intensity-modulated proton therapy (IMPT) and passive scattered proton therapy (PSPT) technique, termed HimpsPT, could be adopted as an alternative delivery method for patients demanding scanning beam proton therapy. PATIENTS AND METHODS: We identified 3 representative clinical cases-an oropharyngeal cancer, skull base chordoma, and stage III non-small-cell lung cancer-that had been treated with IMPT at our center. We retrospectively redesigned these cases using HimpsPT. The PSPT plans for all three cases were designed with the same prescriptions as those used in the IMPT plans. In this way, the whole treatment was delivered using alternating or sequential PSPT and IMPT. RESULTS: All HimpsPT plans met the clinical dose criteria and were of similar quality as the IMPT plans. In the skull base case, the mixed plan was more effective at sparing the brain stem because the sharp penumbra of the aperture in the PSPT plans was not present in the IMPT plans. The HimpsPT plans were more robust than the clinical IMPT plans generated without robust optimization. CONCLUSION: The HimpsPT delivery technique can achieve a treatment-plan quality similar to that of IMPT, even in the most challenging clinical cases. In addition, at centers equipped with both scattering and scanning beam capabilities, the HimpsPT technique may allow more patients to benefit from scanning beam technology.

A Retrospective Evaluation of the Benefit of Referring Pediatric Cancer Patients to an External Proton Therapy Center.

BACKGROUND: Pediatric cancer patients requiring radiation therapy (RT) have been routinely assessed and referred to proton therapy (PT) at an external institution. The benefit of the delivered PT compared to the state-of-the-art intensity modulated x-ray RT (XT) at the home institution was evaluated. PROCEDURE: Twenty-four consecutive children referred for PT during 2010-2013 for craniospinal (CSI, n = 10), localized intracranial (IC, n = 7), head/neck (HN, n = 4) or parameningeal (PM, n = 3) lesions were included. The median age was 8 years (2-16 years). XT plans were generated for each patient, blinded to the PT delivered. Dosimetry, estimated growth hormone deficiency (GHD), and neurocognitive dysfunction (NCD) risks were compared for PT and XT (Wilcoxon). RESULTS: PT started (median) 5 weeks (± 1.3 weeks, 95% CI) after referral. For CSI patients, PT was clearly superior to XT plans with median dose reductions for the heart, lungs and thyroid of 17, 2.5 and 18 Gy, respectively (P = 0.005). The median estimated NCD and GHD risks were 1-3 (max 16) and 2 (max 61) percentage points, respectively, lower for PT compared to XT. The median of the mean doses to the brain, cochleae and pituitary gland was lower with PT than XT for the IC, H/N and PM patients (P < 0.039). For a single IC patient, the dose to hippocampi and optic chiasm was higher for PT compared to XT. CONCLUSIONS: PT clearly benefitted the patients studied, except for IC disease where differences between PT and XT were modest, and comparative PT and XT treatment planning is warranted prior to referral.

Evaluation and mitigation of the interplay effects of intensity modulated proton therapy for lung cancer in a clinical setting.

PURPOSE: The primary aim of this study was to evaluate the impact of the interplay effects of intensity modulated proton therapy (IMPT) plans for lung cancer in the clinical setting. The secondary aim was to explore the technique of isolayered rescanning to mitigate these interplay effects. METHODS AND MATERIALS: A single-fraction 4-dimensional (4D) dynamic dose without considering rescanning (1FX dynamic dose) was used as a metric to determine the magnitude of dosimetric degradation caused by 4D interplay effects. The 1FX dynamic dose was calculated by simulating the machine delivery processes of proton spot scanning on a moving patient, described by 4D computed tomography during IMPT delivery. The dose contributed from an individual spot was fully calculated on the respiratory phase that corresponded to the life span of that spot, and the final dose was accumulated to a reference computed tomography phase by use of deformable image registration. The 1FX dynamic dose was compared with the 4D composite dose. Seven patients with various tumor volumes and motions were selected for study. RESULTS: The clinical target volume (CTV) prescription coverage for the 7 patients was 95.04%, 95.38%, 95.39%, 95.24%, 95.65%, 95.90%, and 95.53% when calculated with the 4D composite dose and 89.30%, 94.70%, 85.47%, 94.09%, 79.69%, 91.20%, and 94.19% when calculated with the 1FX dynamic dose. For these 7 patients, the CTV coverage calculated by use of a single-fraction dynamic dose was 95.52%, 95.32%, 96.36%, 95.28%, 94.32%, 95.53%, and 95.78%, with a maximum monitor unit limit value of 0.005. In other words, by increasing the number of delivered spots in each fraction, the degradation of CTV coverage improved up to 14.6%. CONCLUSIONS: A single-fraction 4D dynamic dose without rescanning was validated as a surrogate to evaluate the interplay effects of IMPT for lung cancer in the clinical setting. The interplay effects potentially can be mitigated by increasing the amount of isolayered rescanning in each fraction delivery.

Evaluation of the systematic error in using 3D dose calculation in scanning beam proton therapy for lung cancer.

The objective of this study was to evaluate and understand the systematic error between the planned three-dimensional (3D) dose and the delivered dose to patient in scanning beam proton therapy for lung tumors. Single-field and multifield optimized scanning beam proton therapy plans were generated for ten patients with stage II-III lung cancer with a mix of tumor motion and size. 3D doses in CT datasets for different respiratory phases and the time-weighted average CT, as well as the four-dimensional (4D) doses were computed for both plans. The 3D and 4D dose differences for the targets and different organs at risk were compared using dose-volume histogram (DVH) and voxel-based techniques, and correlated with the extent of tumor motion. The gross tumor volume (GTV) dose was maintained in all 3D and 4D doses, using the internal GTV override technique. The DVH and voxel-based techniques are highly correlated. The mean dose error and the standard deviation of dose error for all target volumes were both less than 1.5% for all but one patient. However, the point dose difference between the 3D and 4D doses was up to 6% for the GTV and greater than 10% for the clinical and planning target volumes. Changes in the 4D and 3D doses were not correlated with tumor motion. The planning technique (single-field or multifield optimized) did not affect the observed systematic error. In conclusion, the dose error in 3D dose calculation varies from patient to patient and does not correlate with lung tumor motion. Therefore, patient-specific evaluation of the 4D dose is important for scanning beam proton therapy for lung tumors.

On the interplay effects with proton scanning beams in stage III lung cancer.

PURPOSE: To assess the dosimetric impact of interplay between spot-scanning proton beam and respiratory motion in intensity-modulated proton therapy (IMPT) for stage III lung cancer. METHODS: Eleven patients were sampled from 112 patients with stage III nonsmall cell lung cancer to well represent the distribution of 112 patients in terms of target size and motion. Clinical target volumes (CTVs) and planning target volumes (PTVs) were defined according to the authors' clinical protocol. Uniform and realistic breathing patterns were considered along with regular- and hypofractionation scenarios. The dose contributed by a spot was fully calculated on the computed tomography (CT) images corresponding to the respiratory phase that the spot is delivered, and then accumulated to the reference phase of the 4DCT to generate the dynamic dose that provides an estimation of what might be delivered under the influence of interplay effect. The dynamic dose distributions at different numbers of fractions were compared with the corresponding 4D composite dose which is the equally weighted average of the doses, respectively, computed on respiratory phases of a 4DCT image set. RESULTS: Under regular fractionation, the average and maximum differences in CTV coverage between the 4D composite and dynamic doses after delivery of all 35 fractions were no more than 0.2% and 0.9%, respectively. The maximum differences between the two dose distributions for the maximum dose to the spinal cord, heart V40, esophagus V55, and lung V20 were 1.2 Gy, 0.1%, 0.8%, and 0.4%, respectively. Although relatively large differences in single fraction, correlated with small CTVs relative to motions, were observed, the authors' biological response calculations suggested that this interfractional dose variation may have limited biological impact. Assuming a hypofractionation scenario, the differences between the 4D composite and dynamic doses were well confined even for single fraction. CONCLUSIONS: Despite the presence of interplay effect, the delivered dose may be reliably estimated using the 4D composite dose. In general the interplay effect may not be a primary concern with IMPT for lung cancers for the authors' institution. The described interplay analysis tool may be used to provide additional confidence in treatment delivery.

Beyond Gaussians: a study of single-spot modeling for scanning proton dose calculation.

Active spot scanning proton therapy is becoming increasingly adopted by proton therapy centers worldwide. Unlike passive-scattering proton therapy, active spot scanning proton therapy, especially intensity-modulated proton therapy, requires proper modeling of each scanning spot to ensure accurate computation of the total dose distribution contributed from a large number of spots. During commissioning of the spot scanning gantry at the Proton Therapy Center in Houston, it was observed that the long-range scattering protons in a medium may have been inadequately modeled for high-energy beams by a commercial treatment planning system, which could lead to incorrect prediction of field size effects on dose output. In this study, we developed a pencil beam algorithm for scanning proton dose calculation by focusing on properly modeling individual scanning spots. All modeling parameters required by the pencil beam algorithm can be generated based solely on a few sets of measured data. We demonstrated that low-dose halos in single-spot profiles in the medium could be adequately modeled with the addition of a modified Cauchy-Lorentz distribution function to a double-Gaussian function. The field size effects were accurately computed at all depths and field sizes for all energies, and good dose accuracy was also achieved for patient dose verification. The implementation of the proposed pencil beam algorithm also enabled us to study the importance of different modeling components and parameters at various beam energies. The results of this study may be helpful in improving dose calculation accuracy and simplifying beam commissioning and treatment planning processes for spot scanning proton therapy.

Characterization of dose impact on IMRT and VMAT from couch attenuation for two Varian couches.

In intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT), the use of posterior oblique beams has become common. Beam attenuation by the treatment couch is not negligible when the couch is in the beam portal. In this study, we established the relationship of relative dose vs. beam angle for two Varian 21EX linacs, one equipped with the Exact couch (standard couch) with sliding side support rails, and the other equipped with the Exact image-guided radiation therapy (IGRT) carbon fiber couch. Measurements were performed using an ion chamber placed at the center of an acrylic cylindrical phantom positioned at the linac isocenter for 6 MV and 18 MV photon beams. Measurements were performed at three different field sizes (3 × 3, 5 × 5, and 10 × 10 cm2), and were repeated with the phantom positioned at different longitudinal locations on the couches. To evaluate beam attenuation by the standard couch in a clinical setting, two test IMRT plans and two test VMAT plans on the standard couch were delivered. The plans were generated with the sliding rails at the "in" position and delivered with the rails at both "in" and "out" positions. The dose difference to the ion chamber was determined. For oblique fields with 6 MV photons, the standard couch attenuated the radiation beam by up to 26.8%, while the carbon fiber IGRT couch attenuated the beam by up to 4.1%. In the clinical evaluation, the highest dose difference between rails set at the "in" and "out" positions was 2.6% in the IMRT case and 2.1% in the VMAT case. The magnitude of potential dose difference has been quantified and could be used for a quick estimation of dose difference due to couch attenuation in IMRT and VMAT.

Measurement of neutron dose equivalent and its dependence on beam configuration for a passive scattering proton delivery system.

PURPOSE: To measure the neutron dose equivalent per therapeutic proton dose (H/D) in a passive scattering proton therapy system and study its dependence on the proton energy, aperture-to-isocenter distance, spread-out Bragg peak (SOBP) width, and field size. METHODS AND MATERIALS: We performed four experiments of varying proton energies, aperture-to-isocenter distances, SOBP widths, and field sizes. Etched track detectors were used to measure the neutron dose equivalent at both an in-field (isocenter, beyond the protons' range) and out-of-field (30 cm lateral to the isocenter) location in air. RESULTS: For a nonmodulated beam with all the protons stopping in the aperture and an aperture-to-isocenter distance of 30 cm, the H/D values measured at the isocenter were approximately 0.3 mSv/Gy for all snouts with a 100-MeV beam. The H/D values increased to 10.7, 14.5, and 15.1 mSv/Gy, respectively, for small, medium, and large snouts when the beam energy increased to 250 MeV. At the out-of-field location, H/D values increased from 0.1 to 2.7, 3.0, and 3.2 mSv/Gy, respectively, for small, medium, and large snouts. When the aperture-to-isocenter distance was changed from 10 to 40 cm, the H/D value at the isocenter dropped 70%. The H/D value doubled for the modulated beam relative to the nonmodulated beam. Open apertures reduced the neutrons produced in the nozzle, but increased those produced in the phantom. CONCLUSIONS: Our data showed that changes in the four factors studied affect the H/D value in predictable ways which permits an estimate of a patient's neutron exposure.

Blind deblurring reconstruction technique with applications in PET imaging.

We developed an empirical PET model taking into account system blurring and a blind iterative reconstruction scheme that estimates both the actual image and the point spread function of the system. Reconstruction images of high quality can be acquired by using the proposed reconstruction technique for both synthetic and experimental data. In the synthetic data study, the algorithm reduces image blurring and preserves the edges without introducing extra artifacts. The localized measurement shows that the performance of the reconstruction image improved by up to 100%. In experimental data studies, the contrast and quality of reconstruction is substantially improved. The proposed method shows promise in tumor localization and quantification.