Multi-institutional Comparison of Intensity Modulated Photon Versus Proton Radiation Therapy in the Management of Squamous Cell Carcinoma of the Anus.

PURPOSE: Concurrent chemoradiation therapy is a curative treatment for squamous cell carcinoma of the anus, but patients can suffer from significant treatment-related toxicities. This study was undertaken to determine whether intensity modulated proton therapy (IMPT) is associated with less acute toxicity than intensity modulated radiation therapy (IMRT) using photons. MATERIALS AND METHODS: We performed a multi-institutional retrospective study comparing toxicity and oncologic outcomes of IMRT versus IMPT. Patients with stage I-IV (for positive infrarenal para-aortic or common iliac nodes only) squamous cell carcinoma of the anus, as defined by the American Joint Committee on Cancer's AJCC Staging Manual, eighth edition, were included. Patients with nonsquamous histology or mixed IMPT and IMRT treatment courses were excluded. Acute nonhematologic toxicities, per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4, were recorded prospectively at all sites. Acute and late toxicities, dose metrics, and oncologic outcomes were compared between IMRT and IMPT using univariable and multivariable statistical methods. To improve the robustness of our analysis, we also analyzed the data using propensity score weighting methods. RESULTS: A total of 208 patients were treated with either IMPT (58 patients) or IMRT (150 patients). Of the 208 total patients, 13% had stage I disease, 36% stage II, 50% stage III, and 1% stage IV. IMPT reduced the volume of normal tissue receiving low-dose radiation but not high-dose radiation to bladder and bowel. There was no significant difference between treatment groups in overall grade 3 or greater acute toxicity (IMRT, 68%; IMPT, 67%; P = .96) or 2-year overall grade 3 or greater late toxicity (IMRT, 3.5%; IMPT, 1.8%; P = .88). There was no significant difference in 2-year progression-free survival (hazard ratio, 0.8; 95% CI, 0.3-2.0). CONCLUSIONS: Despite reducing the volume of normal tissue receiving low-dose radiation, IMPT was not associated with decreased grade 3 or greater acute toxicity as measured by CTCAE. Additional follow-up is needed to assess whether important differences arise in late toxicities and if further prospective evaluation is warranted.

RhoA/ROCK pathway inhibitor ameliorates erectile dysfunction induced by radiation therapy in rats.

OBJECTIVES: Prostate cancer (PCa) treatment with radiation therapy (RT) has an excellent cure rate. However, Radiation-induced Erectile Dysfunction (RiED) is a common and irreversible toxicity impacting quality of life, and there is no FDA approved specific drug for RiED. We previously showed that prostate RT increased RhoA/ROCK signaling in the cavernous nerve (CN) and penile tissues, which may lead to RiED in rats. In this study, we investigated whether RhoA/ROCK pathway inhibition by a specific inhibitor called Hydroxyfasudil (HF) can improve RiED in our well-established rat model. MATERIALS/METHODS: Male Sprague-Dawley rats were randomized to the following groups: sham-RT, HF-only, RT-only, and RT + HF. Rats were either exposed to a single dose of 25 Gy prostate-confined RT or a sham procedure. 10 mg/kg HF or normal saline was injected intraperitoneally. Erectile function was evaluated by intracavernosal pressure (ICP) and mean arterial pressure (MAP) measurements at week 14 post-RT. Cavernous nerve (CN) injury was evaluated by transmission electron microscopy (TEM), and penile tissue fibrosis by Masson trichrome staining (MT). RESULTS: We have found that the HF treatment prior to RT showed significant (p < 0.001) improvement in ICP/MAP ratio, area under the curve, and maximum ICP value, compared to RT-alone rats. Furthermore, RT + HF treated rats exhibited increased CN myelination and decreased axonal atrophy, comparted to RT-only. HF treatment showed significantly decreased penile tissue fibrosis (p < 0.05) compared to RT-alone treated rats. CONCLUSION: Our results provide the first preclinical evidence that targeting RhoA/ROCK pathway by HF may provide a novel therapeutic option for the treatment of RiED.

Online dose delivery verification in small animal image-guided radiotherapy.

PURPOSE: To accomplish novel radiation treatment techniques in preclinical radiation research, small animal image-guided radiotherapy systems have been increasingly integrated into preclinical radiation research over the last decade. Although such systems have sophisticated tools (such as cone-beam computed tomography-based image guidance, robotic couch, treatment planning system (TPS), and electronic portal imaging devices [EPIDs]). To our knowledge, no established technique can perform independent and online verification of the delivered dose during radiotherapy. In this study, we implement an online EPID dosimetry for each administered SA-IGRT fraction in a rat orthotopic model of prostate cancer. METHODS: To verify the accuracy of delivered dose to rat, we compared the two-dimensional (2D) calculated dose distribution by TPS as the planned dose, with online dose distribution estimated using an EPID as the delivered dose. Since image acquisition software was not capable of acquiring integrated images over a long period of time, we used the EPID to estimate dose rate rather than dose. The central axis (CAX) dose rate values at the beam's exit surface were compared. In addition, 2D dose distributions were also compared under different gamma criteria. To verify the accuracy of our EPID dosimetry technique, we measured transit and exit doses with film during animal treatment. In this study, 20-mm cone was used to collimate beam. We previously observed that the EPID response was independent of collimator size for collimator size ≥15-mm, we did not apply for additional correction factor. RESULTS: Comparison of exit CAX dose rate values of TPS-calculated and EPID-estimated showed that the average difference was 3.1%, with a maximum of 9.3%. Results of gamma analysis for 2D comparison indicated an average of 90% passing rate with global gamma criterion of 2 mm/5%. We observed that TPS could not calculate dose accurately in peripheral regions in which the penumbra effect was dominant. Dose rate values estimated by EPID were within 2.1% agreement with film at both the imager plane and the beam's exit surface for 4 randomly selected animals for which film measurement verification was performed. CONCLUSIONS: The small animal radiation research platform (SARRP) system's built-in EPID was utilized to estimate dose delivered to rats at kilovoltage energy x-rays. The results of this study suggest that the EPID is an invaluable tool for verifying delivered dose to small animal to help validate conclusions made from preclinical radiation research.

A failure modes and effects analysis quality management framework for image-guided small animal irradiators: A change in paradigm for radiation biology.

PURPOSE: Image-guided small animal irradiators (IGSAI) are increasingly being adopted in radiation biology research. These animal irradiators, designed to deliver radiation with submillimeter accuracy, exhibit complexity similar to that of clinical radiation delivery systems, including image guidance, robotic stage motion, and treatment planning systems. However, physics expertise and resources are scarcer in radiation biology, which makes implementation of conventional prescriptive QA infeasible. In this study, we apply the failure modes and effect analysis (FMEA) popularized by the AAPM task group 100 (TG-100) report to IGSAI and radiation biological research. METHODS: Radiation biological research requires a change in paradigm where small errors to large populations of animals are more severe than grievous errors that only affect individuals. To this end, we created a new adverse effects severity table adapted to radiation biology research based on the original AAPM TG-100 severity table. We also produced a process tree which outlines the main components of radiation biology studies performed on an IGSAI, adapted from the original clinical IMRT process tree from TG-100. Using this process tree, we created and distributed a preliminary survey to eight expert IGSAI operators in four institutions. Operators rated proposed failure modes for occurrence, severity, and lack of detectability, and were invited to share their own experienced failure modes. Risk probability numbers (RPN) were calculated and used to identify the failure modes which most urgently require intervention. RESULTS: Surveyed operators indicated a number of high (RPN >125) failure modes specific to small animal irradiators. Errors due to equipment breakdown, such as loss of anesthesia or thermal control, received relatively low RPN (12-48) while errors related to the delivery of radiation dose received relatively high RPN (72-360). Errors identified could either be improved by manufacturer intervention (e.g., electronic interlocks for filter/collimator) or physics oversight (errors related to tube calibration or treatment planning system commissioning). Operators identified a number of failure modes including collision between the collimator and the stage, misalignment between imaging and treatment isocenter, inaccurate robotic stage homing/translation, and incorrect SSD applied to hand calculations. These were all relatively highly rated (90-192), indicating a possible bias in operators towards reporting high RPN failure modes. CONCLUSIONS: The first FMEA specific to radiation biology research was applied to image-guided small animal irradiators following the TG-100 methodology. A new adverse effects severity table and a process tree recognizing the need for a new paradigm were produced, which will be of great use to future investigators wishing to pursue FMEA in radiation biology research. Future work will focus on expanding scope of user surveys to users of all commercial IGSAI and collaborating with manufacturers to increase the breadth of surveyed expert operators.

Two-dimensional dose reconstruction using scatter correction of portal images.

CONTEXT: Electronic portal imaging devices (EPIDs) could potentially be useful for patient setup verification and are also increasingly used for dosimetric verification. The accuracy of EPID for dose verification is dependent on the dose-response characteristics, and without a comprehensive evaluation of dose-response characteristics, EPIDs should not be used clinically. AIMS: A scatter correction method is presented which is based on experimental data of a two-dimensional (2D) ion chamber array. An accurate algorithm for 2D dose reconstruction at midplane using portal images for in vivo dose verification has been developed. SUBJECTS AND METHODS: The procedure of scatter correction and dose reconstruction was based on the application of several corrections for beam attenuation, and off-axis factors, measured using a 2D ion chamber array. 2D dose was reconstructed in slab phantom, OCTAVIUS 4D system, and patient, by back projection of transit dose map at EPID-sensitive layer using percentage depth dose data and inverse square. Verification of the developed algorithm was performed by comparing dose values reconstructed in OCTAVIUS 4D system and with that provided by a treatment planning system. RESULTS: The gamma analysis for dose planes within the OCTAVIUS 4D system showed 98% ±1% passing rate, using a 3%/3 mm pass criteria. Applying the algorithm for dose reconstruction in patient pelvic plans showed gamma passing rate of 96% ±2% using the same pass criteria. CONCLUSIONS: An accurate empirical algorithm for 2D patient dose reconstruction has been developed. The algorithm was applied to phantom and patient data sets and is able to calculate dose in the midplane. Results indicate that the EPID dose reconstruction algorithm presented in this work is suitable for clinical implementation.

Mild hyperthermia as a localized radiosensitizer for deep-seated tumors: investigation in an orthotopic prostate cancer model in mice.

OBJECTIVE:: Non-ablative or mild hyperthermia (HT) has been shown in preclinical (and clinical) studies as a localized radiosensitizer that enhances the tumoricidal effects of radiation. Most preclinical in vivo HT studies use subcutaneous tumor models which do not adequately represent clinical conditions (e.g. proximity of normal/critical organs) or replicate the tumor microenvironment-both of which are important factors for eventual clinical translation. The purpose of this work is to demonstrate proof-of-concept of locoregional radiosensitization with superficially applied, radiofrequency (RF)-induced HT in an orthotopic mouse model of prostate cancer. METHODS:: In a 4-arm study, 40 athymic male nude mice were inoculated in the prostate with luciferase-transfected human prostate cancer cells (PC3). Tumor volumes were allowed to reach 150-250 mm3 (as measured by ultrasound) following which, mice were randomized into (i) control (no intervention); (ii) HT alone; (iii) RT alone; and (iv) HT + RT. RF-induced HT was administered (Groups ii and iv) using the Oncotherm LAB EHY-100 device to achieve a target temperature of 41 °C in the prostate. RT was administered ~30 min following HT, using an image-guided small animal radiotherapy research platform. In each case, a dual arc plan was used to deliver 12 Gy to the target in a single fraction. One animal from each cohort was euthanized on Day 10 or 11 after treatment for caspase-9 and caspase-3 Western blot analysis. RESULTS:: The inoculation success rate was 89%. Mean tumor size at randomization (~16 days post-inoculation) was ~189 mm3 . Following the administration of RT and HT, mean tumor doubling times in days were: control = 4.2; HT = 4.5; RT = 30.4; and HT + RT = 33.4. A significant difference (p = 0.036) was noted between normalized nadir volumes for the RT alone (0.76) and the HT + RT (0.40) groups. Increased caspase-3 expression was seen in the combination treatment group compared to the other treatment groups. CONCLUSION:: These early results demonstrate the successful use of external mild HT as a localized radiosensitizer for deep-seated tumors. ADVANCES IN KNOWLEDGE:: We successfully demonstrated the feasibility of administering external mild HT in an orthotopic tumor model and demonstrated preclinical proof-of-concept of HT-based localized radiosensitization in prostate cancer radiotherapy.

A comprehensive geometric quality assurance framework for preclinical microirradiators.

PURPOSE: The mechanical and geometric accuracy of small animal image-guided radiotherapy (SA-IGRT) systems is critical and is affected by a number of system-related factors. Because of the small dimensions involved in preclinical radiotherapy research, such factors can individually and/or cumulatively contribute to significant errors in the small animal radiation research. In this study, we developed and implemented a comprehensive quality assurance (QA) framework for characterizing the mechanical and geometric constancy and accuracy of the small animal radiation research platform (SARRP) system. METHODS: We quantified the accuracy of gantry and stage rotation isocentricity and positional stage translations. We determined the accuracy and symmetry of field sizes formed by collimators. We evaluated collimator assembly system performance by characterization of collimator axis alignment along the beam axis during gantry rotation. Furthermore, we quantified the end-to-end precision and accuracy of image-guided delivery by examining the congruence of intended (e.g., imaging) and actual delivery (measured during experiment) isocenters. RESULTS: The fine and broad beams showed different central axes. The center of the beam was offset toward the cathode (0.22 ± 0.05 mm) when switching the beam from a fine to a broad focus. Larger (custom-made) collimators were more symmetrically centered than smaller (standard) collimators. The field formed by a 1-mm circular collimator was found to deviate from the circular shape, measuring 1.55 mm and 1.25 mm in the X and Y directions, respectively. The 40-mm collimator showed a field that was 1.65 (4.13%) and 1.3 (3.25%) mm smaller than nominal values in the X and Y directions, respectively, and the 30-mm collimator field was smaller by 0.75 mm (2.5%) in the X direction. Results showed that fields formed by other collimators were accurate in both directions and had ≤2% error. The size of the gantry rotation isocenter was 1.45 ± 0.15 mm. While the gantry rotated, lateral and longitudinal isocenter displacements ranged from 0 to -0.34 and -0.44 to 0.33 mm, respectively. Maximum lateral and longitudinal displacements were found at obliques gantry angles of -135° and 45°, respectively. The stage translational accuracies were 0.015, 0.010, and 0 mm in the X, Y, and Z directions, respectively. The size of the stage rotation runout was 2.73 ± 0.3 mm. Maximum displacements of the stage rotational axis were -0.38 (X direction) and -0.26 (Y direction) mm at stage angles of -45° and -135°, respectively. We found that displacements of intended and actual delivery isocenters were 0.24 ± 0.10, 0.12 ± 0.62, and 0.12 ± 0.42 mm in the X, Y, and Z directions, respectively. CONCLUSION: We used the SARRP built-in electronic portal imaging device (EPID) to perform most of the geometric QA tests, demonstrating the utility of the EPID for characterizing the geometric accuracy and precision of the SA-IGRT system. However, in principle, the methodology and tests developed here are applicable to any digital imaging detector available in SA-IGRT systems or film. The flexibility of film allows these tests to be adapted for QA of non-IGRT, cabinet irradiators, which make up many of preclinical small animal irradiators.

Kilovoltage transit and exit dosimetry for a small animal image-guided radiotherapy system using built-in EPID.

PURPOSE: We investigated the potential use of the built-in electronic portal imaging device (EPID) in the small animal radiation research platform (SARRP) as a dosimeter in the kV energy range. To this end, we developed a method for converting portal images to a two-dimensional (2D) dose maps at the detector plane and object's exit surface and validated them against empirical dose measurements. METHODS: We calibrated the SARRP's EPID to measure transit dose. The transit dose map was back-projected to calculate 2D dose distribution at the object's exit surface. The accuracy of transit and exit dose distributions was independently validated with a PinPoint ion chamber (IC) and Gafchromic EBT3 film measurements for a range of radiation dose rates (0.43-2.78 cGy/s), cone sizes (5-40 mm), in a homogeneous phantom of varying thickness (0-50 mm) and in an inhomogeneous phantom containing graphite, cork, air, and aluminum. RESULTS: In-air central axis (CAX) transit dose values measured with the EPID showed close agreement with film and IC measurements. The maximum differences in EPID in-air transit measurements with film or IC measurements were 1%. The EPID was capable of accurately measuring phantom transit dose independently of the attenuating phantom thickness, with average discrepancies of 0.5% and 2.9% with IC and film, respectively, where the maximum difference between the EPID and the IC was 1.8%. The results were slightly worse for film, with maximum differences in 4.9%. Output factor measurements using EPID were within 2.9% of both IC and film measurements. In addition, calculated exit doses agreed with film values within ≤3.1%, for attenuating phantom thicknesses ≥15 mm. The agreement became worse with decreasing phantom thickness; for thicknesses of 10 and 5 mm, agreements were ≤5.7% and ≤6.9%, respectively. Compared to film, transit and exit profiles measured with the EPID showed average differences <2% for both homogeneous and inhomogeneous materials. CONCLUSION: We developed and validated a novel 2D transit/exit dosimetry for a kV SA-IGRT system using an EPID. We verified the accuracy of our method to measure EPID transit and exit dose distributions for a range of dose rates, beam attenuation, and collimation. Our results indicate that the EPID can be used as a simple, convenient device for kV dose delivery verification in small animal radiotherapy.

Development and implementation of EPID-based quality assurance tests for the small animal radiation research platform (SARRP).

PURPOSE: Although small animal image-guided radiotherapy (SA-IGRT) systems are used increasingly in preclinical research, tools for performing routine quality assurance (QA) have not been optimized and are not readily available. Robust, efficient, and reliable QA tools are needed to ensure the accuracy and reproducibility of SA-IGRT systems. Several investigators have reported custom-made phantoms and protocols for SA-IGRT systems QA. These are typically time and resource intensive and are therefore not well suited to the preclinical radiotherapy environment, in which physics support is limited and routine QA is performed by technical staff. We investigated the use of the inbuilt electronic portal imaging device (EPID) to develop and validate routine QA tests and procedures. In this work, we focus on the Xstrahl Small Animal Radiation Research Platform (SARRP) EPID. However, the methodology and tests developed here are applicable to any SA-IGRT system that incorporates an EPID. METHODS: We performed a comprehensive characterization of the dosimetric properties of the camera-based EPID at kilovoltage energies over a 11-month period, including detector warm-up time, radiation dose history effect, stability and short- and long-term reproducibility, gantry angle dependency, output factor, and linearity of the EPID response. We developed a test to measure the constancy of beam quality in terms of half-value layer and tube peak potential using the EPID. We verified the SARRP daily output and beam profile constancy using the imager. We investigated the use of the imager to monitor beam-targeting accuracy at various gantry and couch angles. RESULTS: The EPID response was stable and reproducible, exhibiting maximum variations of ≤0.3% and ≤1.9% for short and long terms, respectively. The detector showed no dependence on response at different gantry angles, with a maximum variation ≤0.5%. We found close agreement in output factor measurement between the portal imager and reference dosimeters, with maximum differences ≤3% for ionization chamber and ≤1.7% for Gafchromic EBT3 dosimetry film, respectively. We have shown that the EPID response is linear with tube current (mA) for the entire range of tube kilovoltage peak. Notably, a close relationship was seen between the detector response vs mA slope, and the kilovoltage peak, allowing an independent verification of kilovoltage peak stability based solely on EPID response. In addition to dosimetry tests, according to the beam-targeting measurement using portal images, maximum displacement of the central axis of the x-ray beam (due to sag) was 0.76 ± 0.09 mm at gantry 135°/couch 0° and 0.89 ± 0.06 mm at gantry 0°/couch -135°. CONCLUSION: We performed the first comprehensive analysis on the dosimetric properties of an EPID operating at kilovoltage x-ray energies. We characterized the detector performance over a 11-month period. Our results indicate that the imager is a stable and convenient tool for SARRP routine QA tests. We then developed EPID-based tests to perform routine SA-IGRT systems QA tasks, such as verifying constancy of beam quality, energy, output, and profile measurements, relative output factors, and beam targeting.

Dose response characteristics of a novel CCD camera-based electronic portal imaging device comparison with OCTAVIUS detector.

AIM: Dosimetric properties of a CCD camera-based Electronic Portal Imaging Device (EPID) for clinical dosimetric application have been evaluated. Characteristics obtained by EPID also compared with commercial 2D array of ion chambers. MATERIALS AND METHODS: Portal images acquired in dosimetry mode then exported raw fluence or uncorrected images were investigated. Integration time of image acquisition mode has adjusted on 1 s per frame. RESULTS: As saturation of camera of the EPID, dose response does not have linear behavior. The slight nonlinearity of the camera response can be corrected by a logarithmic expression. A fourth order polynomial regression model with coefficient of determination of 0.998 predicts a response to absolute dose values at less than 50 cGy. A field size dependent response of up to 7% (0.99-1.06) relative OCTAVIUS detector measurement was found. The EPID response can be fitted by a cubic regression for field size changes, yielded coefficient of determination of 0.999. CONCLUSIONS: These results indicate that the EPID is well suited for accurate dosimetric purposes, the major limitation currently being due to integration time and dead-time in frame acquisition.

Production, Quality Control and Pharmacokinetic Studies of (177)Lu-EDTMP for Human Bone Pain Palliation Therapy Trials.

Developing new bone pain palliation agents is a mandate in handling end-stage cancer patients around the world. Possibly, Lu-177 ethylenediaminetetramethylene phosphonic acid ((177)Lu-EDTMP) is a therapeutic agent which can be widely used in bone palliation therapy. In this study, (177)Lu-EDTMP complex was prepared successfully using synthesized EDTMP ligand and (177)LuCl3. Lu-177 chloride was obtained by thermal neutron irradiation (4 × 10(13) n.cm(-2)s(-1)) of natural Lu2O3 samples. Radiochemical purity of (177)Lu-EDTMP was determined by ITLC (more than 99%). Stability studies of the final preparations in the presence of human serum were performed. The biodistribution of (177)Lu-EDTMP and (177)LuCl3 in wild-type rats was studied by SPECT imaging. A comparative accumulation study for (177)Lu-EDTMP and (177)LuCl3 was performed for vital organs up to 7 days. The complex was obtained in high radiochemical purity (more than 99%). The complex was stable in vitro in presence of human serum as well as final formulation. Significant bone uptake (> 70%) was observed for the radiopharmaceutical. Due to better physical properties of Lu-177 compared to Sm-153 and acceptable biodistribution results of the compound, (177)Lu-EDTMP seemed to be an interesting new candidate for clinical trials for bone pain palliation therapy.

Development of (166)Ho-phytate Complex for Radiosynovectomy.

BACKGROUND: (66)Ho-chloride was obtained by bombardment of natural Ho(NO3)3 dissolved in acidic media using thermal neutron flux (4-5 × 10(13) n.cm(-2).s(-1)). METHODS: (166)Ho-holmium chloride (185 MBq) was used successfully for preparation of (166)Ho-phytate complex with high radiochemical purity (>99.9 %, ITLC, MeOH: H2O: acetic acid, 4: 4: 2, as mobile phase). The complex stability and viscosity were checked in the final solution up to 2 days. The prepared complex solution (60 µCi/100 µl) was injected intraarticularly to male rat knee joints. Leakage of radioactivity from the injection site and its distribution in organs were investigated up to 2 days. RESULTS: Approximately all of the injected dose had remained in the injection site 2 days after injection. CONCLUSION: The complex was proved to be a feasible agent for cavital radiotherapy in oncology and rheumatology.