Proton stereotactic body radiation therapy for liver metastases-results of 5-year experience for 81 hepatic lesions.

BACKGROUND: To report on our institutional experience using Proton stereotactic body radiation therapy (SBRT) for patients with liver metastases. METHODS: All patients with liver metastases treated with Proton SBRT between September 2012 and December 2017 were retrospectively analyzed. Local control (LC) and overall survival (OS) were estimated using the Kaplan-Meier method calculated from the time of completion of Proton SBRT. LC was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. RESULTS: Forty-six patients with 81 lesions were treated with Proton SBRT. The median age was 65.5 years old (range, 33-86 years) and the median follow up was 15 months (range, 1-54 months). The median size of the gross tumor volume (GTV) was 2.5 cm (range, 0.7-8.9 cm). Two or more lesions were treated in 56.5% of patients, with one patient receiving treatment to a total of five lesions. There were 37 lesions treated with a biologically effective dose (BED) ≤60, 9 lesions with a BED of 61-80, 22 lesions with a BED of 81-100, and 13 lesions with a BED >100. The 1-year and 2-year LC for all lesions was 92.5% (95% CI, 82.7% to 96.8%). The grade 1 and grade 2 toxicity rates were 37% and 6.5%, respectively. There were no grade 3 or higher toxicities and no cases of radiation-induced liver disease (RILD). CONCLUSIONS: Proton SBRT for the treatment of liver metastases has promising LC rates with the ability to safely treat multiple liver metastases. Accrual continues for our phase II trial treating liver metastases with Proton SBRT to 60 GyE (Gray equivalent) in 3 fractions.

A phase I trial of Proton stereotactic body radiation therapy for liver metastases.

BACKGROUND: A phase I trial to determine the maximum tolerated dose (MTD) of Proton stereotactic body radiation therapy (SBRT) for liver metastases in anticipation of a subsequent phase II study. METHODS: An institutional IRB approved phase I clinical trial was conducted. Eligible patients had 1-3 liver metastases measuring less than 5 cm, and no metastases location within 2 cm of the GI tract. Dose escalation was conducted with three dose cohorts. The low, intermediate, and high dose cohorts were planned to receive 36, 48, and 60 respectively to the internal target volume (ITV) in 3 fractions. At least 700 mL of normal liver had to receive <15. Dose-limiting toxicity (DLT) included acute grade 3 liver, intestinal or spinal cord toxicity or any grade 4 toxicity. The MTD is defined as the dose level below that which results in DLT in 2 or more of the 6 patients in the highest dose level cohort. RESULTS: Nine patients were enrolled (6 male, 3 female): median age 64 years (range, 33-77 years); median gross tumor volume (GTV) 11.1 mL (range, 2.14-89.3 mL); most common primary site, colorectal (5 patients). Four patients had multiple tumors. No patient experienced a DLT and dose was escalated to 60 in 3 fractions without reaching MTD. The only toxicity within 90 days of completion of treatment was one patient with a grade 1 skin hyperpigmentation without tenderness or desquamation. Two patients in the low dose cohort had local recurrence and repeat SBRT was done to previously treated lesions without any toxicities. CONCLUSIONS: Biologically ablative Proton SBRT doses are well tolerated in patients with limited liver metastases with no patients experiencing any grade 2+ acute toxicity. Results from this trial provide the grounds for an ongoing phase II Proton SBRT study of 60 over 3 fractions for liver metastases.

Passive proton therapy vs. IMRT planning study with focal boost for prostate cancer.

BACKGROUND: Exploiting biologic imaging, studies have been performed to boost dose to gross intraprostatic tumor volumes (GTV) while reducing dose elsewhere in the prostate. Interest in proton beams has increased due to superior normal-tissue sparing they afford. Our goal was to dosimetrically compare 3D conformal proton boost plans with intensity-modulated radiation therapy (IMRT) plans with respect to target coverage and avoiding organs at risk. METHODS: Treatment planning computer tomography scans of ten patients were selected. For each patient, two hypothetical but realistic GTVs each with a fixed volume were contoured in different anatomical locations of the prostate. IMRT and proton beam plans were created with a prescribed dose of 50.4 Gy to the initial planning target volume (PTV) including the PTV of the seminal vesicles (PSV), 70.2 Gy to the PTV of the prostate (PPS), and 90 Gy to the PTV of the gross tumor volumes (PGTVs). For proton plans, uncertainties of range and patient setup were accounted for; apertures were adjusted until the dose-volume coverage of PTVs matched that of the IMRT plan. For both plans, prescribed PTV doses were made identical to allow for comparing normal-tissue doses. RESULTS: Protons delivered more homogeneous but less conformal doses to PGTVs than IMRT did and comparable doses to PSV and PPS. Volumes of bladder and rectum receiving doses higher than 65 Gy were similar for both plans. However, volumes receiving less than 65 Gy were significantly reduced, i.e., protons reduced integral dose by 45.6 % and 26.5 % for rectum and bladder, respectively. This volume-sparing was also seen in femoral heads and penile bulb. CONCLUSIONS: Protons delivered comparable doses to targets in dose homogeneity and conformity and spared normal tissues from intermediate-to-low doses better than IMRT did. Further improvement of dose sparing and changes in homogeneity and conformity may be achieved by reducing proton range uncertainties and from implementing intensity modulation.

Commissioning of a proton gantry equipped with dual x-ray imagers and a robotic patient positioner, and evaluation of the accuracy of single-beam image registration for this system.

PURPOSE: To check the accuracy of a gantry equipped with dual x-ray imagers and a robotic patient positioner for proton radiotherapy, and to evaluate the accuracy and feasibility of single-beam registration using the robotic positioner. METHODS: One of the proton treatment rooms at their institution was upgraded to include a robotic patient positioner (couch) with 6 degrees of freedom and dual orthogonal kilovoltage x-ray imaging panels. The wander of the proton beam central axis, the wander of the beamline, and the orthogonal image panel crosswires from the gantry isocenter were measured for different gantry angles. The couch movement accuracy and couch wander from the gantry isocenter were measured for couch loadings of 50-300 lb with couch rotations from 0° to ± 90°. The combined accuracy of the gantry, couch, and imagers was checked using a custom-made 30 × 30 × 30 cm(3) Styrofoam phantom with beekleys embedded in it. A treatment in this room can be set up and registered at a setup field location, then moved precisely to any other treatment location without requiring additional image registration. The accuracy of the single-beam registration strategy was checked for treatments containing multiple beams with different combinations of gantry angles, couch yaws, and beam locations. RESULTS: The proton beam central axis wander from the gantry isocenter was within 0.5 mm with gantry rotations in both clockwise (CW) and counterclockwise (CCW) directions. The maximum wander of the beamline and orthogonal imager crosswire centers from the gantry isocenter were within 0.5 and 0.8 mm, respectively, with the gantry rotations in CW and CCW directions. Vertical and horizontal couch wanders from the gantry isocenter were within 0.4 and 1.3 mm, respectively, for couch yaw from 0° to ± 90°. For a treatment with multiple beams with different gantry angles, couch yaws, and beam locations, the measured displacements of treatment beam locations from the one based on the initial setup beam registered at the gantry at 0°/180° and couch yaw at 0° were within 1.5 mm in three translations and 0.5° in three rotations for a 200 lb couch loading. CONCLUSIONS: Results demonstrate that the gantry equipped with a robotic patient positioner and dual imaging panels satisfies treatment requirements for proton radiotherapy. The combined accuracy of the gantry, couch, and imagers allows a patient to be registered at one setup position and then moved precisely to another treatment position by commanding the robotic patient positioner and delivering treatment without requiring additional image registration.

Radiographic film dosimetry of proton beams for depth-dose constancy check and beam profile measurement.

Radiographic film dosimetry suffers from its energy dependence in proton dosimetry. This study sought to develop a method of measuring proton beams by the film and to evaluate film response to proton beams for the constancy check of depth dose (DD). It also evaluated the film for profile measurements. To achieve this goal, from DDs measured by film and ion chamber (IC), calibration factors (ratios of dose measured by IC to film responses) as a function of depth in a phantom were obtained. These factors imply variable slopes (with proton energy and depth) of linear characteristic curves that relate film response to dose. We derived a calibration method that enables utilization of the factors for acquisition of dose from film density measured at later dates by adapting to a potentially altered processor condition. To test this model, the characteristic curve was obtained by using EDR2 film and in-phantom film dosimetry in parallel with a 149.65 MeV proton beam, using the method. An additional validation of the model was performed by concurrent film and IC measurement perpendicular to the beam at various depths. Beam profile measurements by the film were also evaluated at the center of beam modulation. In order to interpret and ascertain the film dosimetry, Monte Carlos simulation of the beam was performed, calculating the proton fluence spectrum along depths and off-axis distances. By multiplying respective stopping powers to the spectrum, doses to film and water were calculated. The ratio of film dose to water dose was evaluated. Results are as follows. The characteristic curve proved the assumed linearity. The measured DD approached that of IC, but near the end of the spread-out Bragg peak (SOBP), a spurious peak was observed due to the mismatch of distal edge between the calibration and measurement films. The width of SOBP and the proximal edge were both reproducible within a maximum of 5mm; the distal edge was reproducible within 1 mm. At 5 cm depth, the dose was reproducible within 10%. These large discrepancies were identified to have been contributed by film processor uncertainty across a layer of film and the misalignment of film edge to the frontal phantom surface. The deviations could drop from 5 to 2 mm in SOBP and from 10% to 4.5% at 5 cm depth in a well-controlled processor condition(i.e., warm up). In addition to the validation of the calibration method done by the DD measurements, the concurrent film and IC measurement independently validated the model by showing the constancy of depth-dependent calibration factors. For profile measurement, the film showed good agreement with ion chamber measurement. In agreement with the experimental findings, computationally obtained ratio of film dose to water dose assisted understanding of the trend of the film response by revealing relatively large and small variances of the response for DD and beam profile measurements, respectively. Conclusions are as follows. For proton beams, radiographic film proved to offer accurate beam profile measurements. The adaptive calibration method proposed in this study was validated. Using the method, film dosimetry could offer reasonably accurate DD constancy checks, when provided with a well-controlled processor condition. Although the processor warming up can promote a uniform processing across a single layer of the film, the processing remains as a challenge.

Evaluation of normal tissue exposure in patients receiving radiotherapy for pancreatic cancer based on RTOG 0848.

BACKGROUND: Pancreatic cancer is a highly aggressive malignancy. Chemoradiotherapy (CRT) is utilized in many cases to improve locoregional control; however, toxicities associated with radiation can be significant given the location of the pancreas. RTOG 0848 seeks to evaluate chemoradiation using either intensity-modulated radiation therapy (IMRT) or 3D conformal photon radiotherapy (3DCRT) modalities as an adjuvant treatment. The purpose of this study is to quantify the dosimetric changes seen when using IMRT or 3D CRT photon modalities, as well as proton radiotherapy, in patients receiving CRT for cancer of the pancreas treated per RTOG 0848 guidelines. MATERIALS: Ten patients with pancreatic head adenocarcinoma treated between 2010 and 2013 were evaluated in this study. All patients were simulated with contrast-enhanced CT imaging. Separate treatment plans using IMRT and 3DCRT as well as proton radiotherapy were created for each patient. All planning volumes were created per RTOG 0848 protocol. Dose-volume histograms (DVH) were calculated and analyzed in order to compare plans between the three modalities. The organs at risk (OAR) evaluated in this study are the kidneys, liver, small bowel, and spinal cord. RESULTS: There was no difference between the IMRT and 3DCRT plans in dose delivered to the kidneys, liver, or bowel. The proton radiotherapy plans were found to deliver lower mean total kidney doses, mean liver doses, and liver D1/3 compared to the IMRT plans. The proton plans also gave less mean liver dose, liver D1/3, bowel V15, and bowel V50 in comparison to the 3DCRT. CONCLUSIONS: For patients receiving radiotherapy per ongoing RTOG 0848 for pancreatic cancer, there was no significant difference in normal tissue sparing between IMRT and 3DCRT treatment planning. Therefore, the choice between the two modalities should not be a confounding factor in this study. The proton plans also demonstrated improved OAR sparing compared to both IMRT and 3DCRT treatment plans.

Analysis of Intensity-Modulated Radiation Therapy (IMRT), Proton and 3D Conformal Radiotherapy (3D-CRT) for Reducing Perioperative Cardiopulmonary Complications in Esophageal Cancer Patients.

Background. While neoadjuvant concurrent chemoradiotherapy has improved outcomes for esophageal cancer patients, surgical complication rates remain high. The most frequent perioperative complications after trimodality therapy were cardiopulmonary in nature. The radiation modality utilized can be a strong mitigating factor of perioperative complications given the location of the esophagus and its proximity to the heart and lungs. The purpose of this study is to make a dosimetric comparison of Intensity-Modulated Radiation Therapy (IMRT), proton and 3D conformal radiotherapy (3D-CRT) with regard to reducing perioperative cardiopulmonary complications in esophageal cancer patients. Materials. Ten patients with esophageal cancer treated between 2010 and 2013 were evaluated in this study. All patients were simulated with contrast-enhanced CT imaging. Separate treatment plans using proton radiotherapy, IMRT, and 3D-CRT modalities were created for each patient. Dose-volume histograms were calculated and analyzed to compare plans between the three modalities. The organs at risk (OAR) being evaluated in this study are the heart, lungs, and spinal cord. To determine statistical significance, ANOVA and two-tailed paired t-tests were performed for all data parameters. Results. The proton plans showed decreased dose to various volumes of the heart and lungs in comparison to both the IMRT and 3D-CRT plans. There was no difference between the IMRT and 3D-CRT plans in dose delivered to the lung or heart. This finding was seen consistently across the parameters analyzed in this study. Conclusions. In patients receiving radiation therapy for esophageal cancer, proton plans are technically feasible while achieving adequate coverage with lower doses delivered to the lungs and cardiac structures. This may result in decreased cardiopulmonary toxicity and less morbidity to esophageal cancer patients.

Partial breast radiation therapy with proton beam: 5-year results with cosmetic outcomes.

PURPOSE: We updated our previous report of a phase 2 trial using proton beam radiation therapy to deliver partial breast irradiation (PBI) in patients with early stage breast cancer. METHODS AND MATERIALS: Eligible subjects had invasive nonlobular carcinoma with a maximal dimension of 3 cm. Patients underwent partial mastectomy with negative margins; axillary lymph nodes were negative on sampling. Subjects received postoperative proton beam radiation therapy to the surgical bed. The dose delivered was 40 Gy in 10 fractions, once daily over 2 weeks. Multiple fields were treated daily, and skin-sparing techniques were used. Following treatment, patients were evaluated with clinical assessments and annual mammograms to monitor toxicity, tumor recurrence, and cosmesis. RESULTS: One hundred subjects were enrolled and treated. All patients completed the assigned treatment and were available for post-treatment analysis. The median follow-up was 60 months. Patients had a mean age of 63 years; 90% had ductal histology; the average tumor size was 1.3 cm. Actuarial data at 5 years included ipsilateral breast tumor recurrence-free survival of 97% (95% confidence interval: 100%-93%); disease-free survival of 94%; and overall survival of 95%. There were no cases of grade 3 or higher acute skin reactions, and late skin reactions included 7 cases of grade 1 telangiectasia. Patient- and physician-reported cosmesis was good to excellent in 90% of responses, was not changed from baseline measurements, and was well maintained throughout the entire 5-year follow-up period. CONCLUSIONS: Proton beam radiation therapy for PBI produced excellent ipsilateral breast recurrence-free survival with minimal toxicity. The treatment proved to be adaptable to all breast sizes and lumpectomy cavity configurations. Cosmetic results appear to be excellent and unchanged from baseline out to 5 years following treatment. Cosmetic results may be improved over those reported with photon-based techniques due to reduced breast tissue exposure with proton beam, skin-sparing techniques, and the dose fractionation schedule used in this trial.

Conditions for reliable time-resolved dosimetry of electronic portal imaging devices for fixed-gantry IMRT and VMAT.

PURPOSE: The continuous scanning mode of electronic portal imaging devices (EPID) that offers time-resolved information has been newly explored for verifying dynamic radiation deliveries. This study seeks to determine operating conditions (dose rate stability and time resolution) under which that mode can be used accurately for the time-resolved dosimetry of intensity-modulated radiation therapy (IMRT) beams. METHODS: The authors have designed the following test beams with variable beam holdoffs and dose rate regulations: a 10 × 10 cm open beam to serve as a reference beam; a sliding window (SW) beam utilizing the motion of a pair of multileaf collimator (MLC) leaves outside the 10 × 10 cm jaw; a step and shoot (SS) beam to move the pair in step; a volumetric modulated arc therapy (VMAT) beam. The beams were designed in such a way that they all produce the same open beam output of 10 × 10 cm. Time-resolved ion chamber measurements at isocenter and time-resolved and integrating EPID measurements were performed for all beams. The time-resolved EPID measurements were evaluated through comparison with the ion chamber and integrating EPID measurements, as the latter are accepted procedures. For two-dimensional, time-resolved evaluation, a VMAT beam with an infield MLC travel was designed. Time-resolved EPID measurements and Monte Carlo calculations of such EPID dose images for this beam were performed and intercompared. RESULTS: For IMRT beams (SW and SS), the authors found disagreement greater than 2%, caused by frame missing of the time-resolved mode. However, frame missing disappeared, yielding agreement better than 2%, when the dose rate of irradiation (and thus the frame acquisition rates) reached a stable and planned rate as the dose of irradiation was raised past certain thresholds (a minimum 12 s of irradiation per shoot used for SS IMRT). For VMAT, the authors found that dose rate does not affect the frame acquisition rate, thereby causing no frame missing. However, serious inplanar nonuniformities were found. This could be overcome by sacrificing temporal resolution (10 frames or 0.95 s/image): the continuous images agreed with ion chamber responses at the center of EPID and the calculation two-dimensionally in a time-resolved manner. CONCLUSIONS: The authors have determined conditions under which the continuous mode can be used for time-resolved dosimetry of fixed-gantry IMRT and VMAT and demonstrated it for VMAT.

Evaluation and comparison of New 4DCT based strategies for proton treatment planning for lung tumors.

PURPOSE: To evaluate different strategies for proton lung treatment planning based on four-dimensional CT (4DCT) scans. METHODS AND MATERIALS: Twelve cases, involving only gross tumor volumes (GTV), were evaluated. Single image sets of (1) maximum intensity projection (MIP3) of end inhale (EI), middle exhale (ME) and end exhale (EE) images; (2) average intensity projection (AVG) of all phase images; and (3) EE images from 4DCT scans were selected as primary images for proton treatment planning. Internal target volumes (ITVs) outlined by a clinician were imported into MIP3, AVG, and EE images as planning targets. Initially, treatment uncertainties were not included in planning. Each plan was imported into phase images of 4DCT scans. Relative volumes of GTVs covered by 95% of prescribed dose and mean ipsilateral lung dose of a phase image obtained by averaging the dose in inspiration and expiration phases were used to evaluate the quality of a plan for a particular case. For comparing different planning strategies, the mean of the averaged relative volumes of GTVs covered by 95% of prescribed dose and its standard deviation for each planning strategy for all cases were used. Then, treatment uncertainties were included in planning. Each plan was recalculated in phase images of 4DCT scans. Same strategies were used for plan evaluation except dose-volume histograms of the planning target volumes (PTVs) instead of GTVs were used and the mean and standard deviation of the relative volumes of PTVs covered by 95% of prescribed dose and the ipsilateral lung dose were used to compare different planning strategies. RESULTS: MIP3 plans without treatment uncertainties yielded 96.7% of the mean relative GTV covered by 95% of prescribed dose (standard deviations of 5.7% for all cases). With treatment uncertainties, MIP3 plans yielded 99.5% of mean relative PTV covered by 95% of prescribed dose (standard deviations of 0.7%). Inclusion of treatment uncertainties improved PTV dose coverage but also increased the ipsilateral mean lung dose in general, and reduced the variations of the PTV dose coverage among different cases. Plans based on conventional axial CT scan (CVCT) gave the poorest PTV dose coverage (about 96% of mean relative PTV covered by 95% isodose) compared to MIP3 and EE plans, which resulted in 100% of PTV covered by 95% isodose for tumors with relatively large motion. AVG plans demonstrated PTV dose coverage of 89.8% and 94.4% for cases with small tumors. MIP3 plans demonstrated superior tumor coverage and were least sensitive to tumor size and tumor location. CONCLUSION: MIP3 plans based on 4DCT scans were the best planning strategy for proton lung treatment planning.

Fractionated proton radiotherapy for benign cavernous sinus meningiomas.

PURPOSE: To evaluate the efficacy of fractionated proton radiotherapy for a population of patients with benign cavernous sinus meningiomas. METHODS AND MATERIALS: Between 1991 and 2002, 72 patients were treated at Loma Linda University Medical Center with proton therapy for cavernous sinus meningiomas. Fifty-one patients had biopsy or subtotal resection; 47 had World Health Organization grade 1 pathology. Twenty-one patients had no histologic verification. Twenty-two patients received primary proton therapy; 30 had 1 previous surgery; 20 had more than 1 surgery. The mean gross tumor volume was 27.6 cm(3); mean clinical target volume was 52.9 cm(3). Median total doses for patients with and without histologic verification were 59 and 57 Gy, respectively. Mean and median follow-up periods were 74 months. RESULTS: The overall 5-year actuarial control rate was 96%; the control rate was 99% in patients with grade 1 or absent histologic findings and 50% for those with atypical histology. All 21 patients who did not have histologic verification and 46 of 47 patients with histologic confirmation of grade 1 tumor demonstrated disease control at 5 years. Control rates for patients without previous surgery, 1 surgery, and 2 or more surgeries were 95%, 96%, and 95%, respectively. CONCLUSIONS: Fractionated proton radiotherapy for grade 1 cavernous sinus meningiomas achieves excellent control rates with minimal toxicities, regardless of surgical intervention or use of histologic diagnosis. Disease control for large lesions can be achieved by primary fractionated proton therapy.

A practical approach for electron monitor unit calculation.

Electron monitor unit (MU) calculation requires measured beam data such as the relative output factor (ROF) of a cone, insert correction factor (ICF) and effective source-to-surface distance (ESD). Measuring the beam data to cover all possible clinical cases is not practical for a busy clinic because it takes tremendous time and labor. In this study, we propose a practical approach to reduce the number of data measurements without affecting accuracy. It is based on two findings of dosimetric properties of electron beams. One is that the output ratio of two inserts is independent of the cone used, and the other is that ESD is a function of field size but independent of cone and jaw opening. For the measurements to prove the findings, a parallel plate ion chamber (Markus, PTW 23343) with an electrometer (Cardinal Health 35040) was used. We measured the outputs to determine ROF, ICF and ESD of different energies (5-21 MeV). Measurements were made in a Plastic Water phantom or in water. Three linear accelerators were used: Siemens MD2 (S/N 2689), Siemens Primus (S/N 3305) and Varian Clinic 21-EX (S/N 1495). With these findings, the number of data set to be measured can be reduced to less than 20% of the data points.

Dosimetry aspects of proton therapy.

High-energy photons and high-energy protons are very different in the ways they interact with matter. These differences lead to distinct advantages of protons over photons for treatment of cancer. Some aspects of proton interactions with tissue that make this modality superior for treating cancer are: (i) Initially, the protons lose energy very slowly as they enter the body; this results in a low entrance dose and low doses to the normal tissues proximal to the tumor. (ii) Near the end of range, protons lose energy very rapidly and deposit all their energy over a very small volume before they come to rest. This is the Bragg peak, a property that results in delivery of the maximum dose to the tumor. (iii) Beyond the Bragg peak, the energy deposited by the protons is zero; no dose is received by normal tissues distal to the tumor. Therefore, protons deliver their maximum dose to the tumor, a low dose to normal structures proximal to the tumor, and no dose to the normal structures beyond the tumor, ideal properties of a radiation modality to treat cancer. One distinct advantage of protons over photons is the ease with which the tumor target can be irradiated conformably to a high dose, and at the same time the normal structures in the vicinity of the tumor can be protected conformably from that high dose. Given the same dose to the tumor via photons and protons, protons inherently deliver less integral dose and, thus, lead to fewer normal-tissue complications. In addition, proton interactions also offer distinct radiobiological advantages over photons. Superior physical and radiobiological proton interactions lead naturally to the concepts of dose escalation and hypofractionation. The superiority of treatment delivery with protons as contrasted with photons is demonstrated by treatment plans.