Experience in commissioning the halcyon linac.

PURPOSE: This manuscript describes the experience of two institutions in commissioning the new HalcyonTM platform. Its purpose is to: (a) validate the pre-defined beam data, (b) compare relevant commissioning data acquired independently by two separate institutions, and (c) report on any significant differences in commissioning between the Halcyon linear accelerator and other medical linear accelerators. METHODS: Extensive beam measurements, testing of mechanical and imaging systems, including the multi-leaf collimator (MLC), were performed at the two institutions independently. The results were compared with published recommendations as well. When changes in standard practice were necessitated by the design of the new system, the efficacy of such changes was evaluated as compared to published approaches (guidelines or vendor documentation). RESULTS: Given the proper choice of detectors, good agreement was found between the respective experimental data and the treatment planning system calculations, and between independent measurements by the two institutions. MLC testing, MV imaging, and mechanical system showed unique characteristics that are different from the traditional C-arm linacs. Although the same methodologies and physics equipment can generally be used for commissioning the Halcyon, some adaptation of previous practices and development of new methods were also necessary. CONCLUSIONS: We have shown that the vendor pre-loaded data agree well with the independent measured ones during the commission process. This verifies that a data validation instead of a full-data commissioning process may be a more efficient approach for the Halcyon. Measurement results could be used as a reference for future Halcyon users.

Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair.

The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in non-homologous end-joining (NHEJ) repair. We investigated the mechanism of NU7441, a highly selective DNA-PK inhibitor, in NHEJ-competent mouse embryonic fibroblast (MEF) cells and NHEJ-deficient cells and explored the feasibility of its application in radiosensitizing nasopharyngeal carcinoma (NPC) cells. We generated wild-type and DNA-PKcs-/- MEF cells. Clonogenic survival assays, flow cytometry, and immunoblotting were performed to study the effect of NU7441 on survival, cell cycle, and DNA repair. NU7441 profoundly radiosensitized wild-type MEF cells and SUNE-1 cells, but not DNA-PKcs-/- MEF cells. NU7441 significantly suppressed radiation-induced DSB repair post-irradiation through unrepaired and lethal DNA damage, the cell cycle arrest. The effect was associated with the activation of cell cycle checkpoints. The present study revealed a mechanism by which inhibition of DNA-PK sensitizes cells to irradiation suggesting that radiotherapy in combination with DNA-PK inhibitor is a promising paradigm for the management of NPC which merits further investigation.

Empowering Intensity Modulated Proton Therapy Through Physics and Technology: An Overview.

Considering the clinical potential of protons attributable to their physical characteristics, interest in proton therapy has increased greatly in this century, as has the number of proton therapy installations. Until recently, passively scattered proton therapy was used almost entirely. Notably, the overall clinical results to date have not shown a convincing benefit of protons over photons. A rapid transition is now occurring with the implementation of the most advanced form of proton therapy, intensity modulated proton therapy (IMPT). IMPT is superior to passively scattered proton therapy and intensity modulated radiation therapy (IMRT) dosimetrically. However, numerous limitations exist in the present IMPT methods. In particular, compared with IMRT, IMPT is highly vulnerable to various uncertainties. In this overview we identify three major areas of current limitations of IMPT: treatment planning, treatment delivery, and motion management, and discuss current and future efforts for improvement. For treatment planning, we need to reduce uncertainties in proton range and in computed dose distributions, improve robust planning and optimization, enhance adaptive treatment planning and delivery, and consider how to exploit the variability in the relative biological effectiveness of protons for clinical benefit. The quality of proton therapy also depends on the characteristics of the IMPT delivery systems and image guidance. Efforts are needed to optimize the beamlet spot size for both improved dose conformality and faster delivery. For the latter, faster energy switching time and increased dose rate are also needed. Real-time in-room volumetric imaging for guiding IMPT is in its early stages with cone beam computed tomography (CT) and CT-on-rails, and continued improvements are anticipated. In addition, imaging of the proton beams themselves, using, for instance, prompt γ emissions, is being developed to determine the proton range and to reduce range uncertainty. With the realization of the advances described above, we posit that IMPT, thus empowered, will lead to substantially improved clinical results.

Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a distinct factor in the non-homologous end-joining (NHEJ) pathway involved in DNA double-strand break (DSB) repair. We examined the crosstalk between key proteins in the DSB NHEJ repair pathway and cell cycle regulation and found that mouse embryonic fibroblast (MEF) cells deficient in DNA-PKcs or Ku70 were more vulnerable to ionizing radiation (IR) compared with wild-type cells and that DSB repair was delayed. γH2AX was associated with phospho-Ataxia-telangiectasia mutated kinase (Ser1987) and phospho-checkpoint effector kinase 1 (Ser345) foci for the arrest of cell cycle through the G2/M phase. Inhibition of DNA-PKcs prolonged IR-induced G2/M phase arrest because of sequential activation of cell cycle checkpoints. DSBs were introduced, and cell cycle checkpoints were recruited after exposure to IR in nasopharyngeal carcinoma SUNE-1 cells. NU7441 radiosensitized MEF cells and SUNE-1 cells by interfering with DSB repair. Together, these results reveal a mechanism in which coupling of DSB repair with the cell cycle radiosensitizes NHEJ repair-deficient cells, justifying further development of DNA-PK inhibitors in cancer therapy.

Acquisition of MV-scatter-free kilovoltage CBCT images during RapidArc™ or VMAT.

PURPOSE: To perform kilovoltage (kV) cone beam computed tomography (CBCT) imaging concomitant with the delivery of megavoltage (MV) RapidArc treatment, and demonstrate the feasibility of obtaining MV-scatter-free kV CBCT images. METHODS AND MATERIALS: RapidArc/CBCT treatment and imaging plans are designed, and delivered on the Varian TrueBeam, using its Developer Mode. The plan contains 250 control points for MV-radiation delivery, each over an arc of 0.4-0.7(o). Interlaced between successive MV delivery control points are imaging control points, each over an arc of 0.7-1.1(o). During the 360(o) gantry rotation for the RapidArc delivery, CBCT projections of a phantom are acquired at 11 frames per second. The kV projections with minimal MV-scatter are selected, based on gantry angle, and the CBCT(s) image reconstructed. For comparison, a reference CBCT(r) image is acquired in the normal way. In addition, to examine the effect of MV-scatter we acquire CBCT(c) using the same treatment plan without the imaging control points, i.e. with continuous MV delivery during the 360(o) rotation. Quantitative evaluation of image qualities is performed based on the concepts of CNR (contrast-to-noise ratio) and NSTD (normalized standard deviation). RESULTS: The different types of CBCT images were reconstructed, evaluated, and compared. Visual comparison indicates that the image quality of CBCT(s) is similar to that of the reference CBCT(r), and that the quality of CBCT(c) is significantly degraded by the MV-scatter. Quantitative evaluation of the image quality indicates that MV-scatter significantly decreases the CNR of CBCT (from ∼7 to ∼3.5 in one comparison). Similarly, MV-scatter significantly increases the inhomogeneity of image intensity, e.g. from ∼0.03 to ∼0.06 in one comparison. CONCLUSION: We have developed a method to acquire MV-scatter-free kV CBCT images concomitant with the delivery of RapidArc treatment. Engineering development is necessary to improve the process, e.g. by synchronization of the MV and kV beams.

Report from the Radiation Therapy Committee of the Southwest Oncology Group (SWOG): Research Objectives Workshop 2008.

Strategic planning for the Radiation Therapy Committee of the Southwest Oncology Group (SWOG) is comprehensively evaluated every six years in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2008 Strategic Planning Workshop included clinical trial experts from multiple specialties, industry representatives from both pharmaceuticals and equipment manufacturers, and basic scientists. High-priority research areas such as image-guided radiation therapy for control of limited metastatic disease, analysis of biomarkers for treatment response and late toxicity, assessment of novel agents in combination with radiation, standardization of radiation target delineation, and the assessment of new imaging techniques to individualize cancer therapy, were discussed. Research priorities included clinical study designs featuring translational end points that identify patients most likely to benefit from combined modality therapy; intervention including combination radiation with standard chemotherapy; radiation with radiosensitizing molecular-targeted therapies; and stereotactic radiation for treatment of patients with regard to asymptomatic metastasis and radiation-induced tumor autoimmunity. The Committee concluded that the future research opportunities are among the most exciting to have developed in the last decade, and work is in progress to embark on these plans.

Radiosynthesis of [(131)I]IAZGP via nucleophilic substitution and its biological evaluation as a hypoxia marker - is specific activity a factor influencing hypoxia-mapping ability of a hypoxia marker?

INTRODUCTION: The hypoxia marker IAZGP, 1-(6-deoxy-6-iodo-beta-d-galactopyranosyl)-2-nitroimidazole, has been labeled with (123)I/(124)I/(125)I/(131)I via iodine-radioiodine exchange, which gives the radiotracer in a specific activity of 10-90 MBq/micromol. We synthesized the same radiotracer possessing several hundred to thousand times higher specific activity (high-SA IAZGP) via nucleophilic substitution and compared its biological behavior with that of conventionally produced IAZGP (low-SA IAZGP) to determine if specific activity is a factor influencing cell uptake kinetics, biodistribution and intratumor microregional localization of the radiotracer. METHODS: High-SA [(131)I]IAZGP was prepared by substitution of the tosyl functionality with [(131)I]iodide. In vitro uptake of high- and low-SA [(131)I]IAZGP by HCT8 and HT29 cells was assessed in normoxic and hypoxic conditions. Biodistribution and intratumor localization of high- and low-SA [(131)I]IAZGP were determined by injection into HT29 tumor-bearing mice. RESULTS: The nucleophilic substitution reaction proceeded efficiently in acetonitrile at 150 degrees C, giving the final product in an average yield of 42% and an average specific activity of 30 GBq/micromol. In vitro, high-SA [(131)I]IAZGP was incorporated into the tumor cells with similar kinetics and oxygen dependence to low-SA [(131)I]IAZGP. In HT29 tumor-bearing mice, biodistributions of high- and low-SA [(131)I]IAZGP were equivalent. Ex vivo autoradiography revealed heterogeneous intratumor localization of high-SA [(131)I]IAZGP corresponding closely to distributions of other exogenous and endogenous hypoxia markers. Comparable microregional distribution patterns were observed with low-SA [(131)I]IAZGP. CONCLUSIONS: Radiolabeled IAZGP produced via nucleophilic substitution is validated as an exogenous hypoxia marker. Specific activity does not appear to influence the in vivo hypoxia-mapping ability of the radiotracer.

Reproducibility of intratumor distribution of (18)F-fluoromisonidazole in head and neck cancer.

PURPOSE: Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. (18)F-fluoromisonidazole ((18)F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of (18)F-FMISO intratumor distribution using two pretreatment PET scans. METHODS AND MATERIALS: We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an (18)F-fluorodeoxyglucose study, followed by two (18)F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio >or=1.2. The (18)F-FMISO tracer distributions from the two (18)F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the (18)F-FMISO intensities of the corresponding spatial voxels was derived. RESULTS: A voxel-by-voxel analysis of the (18)F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%. CONCLUSION: Variability in spatial uptake can occur between repeat (18)F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of (18)F-FMISO-suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before single-time-point (18)F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy.

Fluorine-18-labeled fluoromisonidazole positron emission and computed tomography-guided intensity-modulated radiotherapy for head and neck cancer: a feasibility study.

PURPOSE: Hypoxia renders tumor cells radioresistant, limiting locoregional control from radiotherapy (RT). Intensity-modulated RT (IMRT) allows for targeting of the gross tumor volume (GTV) and can potentially deliver a greater dose to hypoxic subvolumes (GTV(h)) while sparing normal tissues. A Monte Carlo model has shown that boosting the GTV(h) increases the tumor control probability. This study examined the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomography/computed tomography ((18)F-FMISO PET/CT)-guided IMRT with the goal of maximally escalating the dose to radioresistant hypoxic zones in a cohort of head and neck cancer (HNC) patients. METHODS AND MATERIALS: (18)F-FMISO was administered intravenously for PET imaging. The CT simulation, fluorodeoxyglucose PET/CT, and (18)F-FMISO PET/CT scans were co-registered using the same immobilization methods. The tumor boundaries were defined by clinical examination and available imaging studies, including fluorodeoxyglucose PET/CT. Regions of elevated (18)F-FMISO uptake within the fluorodeoxyglucose PET/CT GTV were targeted for an IMRT boost. Additional targets and/or normal structures were contoured or transferred to treatment planning to generate (18)F-FMISO PET/CT-guided IMRT plans. RESULTS: The heterogeneous distribution of (18)F-FMISO within the GTV demonstrated variable levels of hypoxia within the tumor. Plans directed at performing (18)F-FMISO PET/CT-guided IMRT for 10 HNC patients achieved 84 Gy to the GTV(h) and 70 Gy to the GTV, without exceeding the normal tissue tolerance. We also attempted to deliver 105 Gy to the GTV(h) for 2 patients and were successful in 1, with normal tissue sparing. CONCLUSION: It was feasible to dose escalate the GTV(h) to 84 Gy in all 10 patients and in 1 patient to 105 Gy without exceeding the normal tissue tolerance. This information has provided important data for subsequent hypoxia-guided IMRT trials with the goal of further improving locoregional control in HNC patients.

Adenovirus-mediated expression of a dominant negative Ku70 fragment radiosensitizes human tumor cells under aerobic and hypoxic conditions.

Ku70 is one component of a protein complex, the Ku70/Ku80 heterodimer, which binds to DNA double-strand breaks and activates DNA-dependent protein kinase (DNA-PK), leading to DNA damage repair. Our previous work has confirmed that Ku70 is important for DNA damage repair in that Ku70 deficiency compromises the ability of cells to repair DNA double-strand breaks, increases the radiosensitivity of cells, and enhances radiation-induced apoptosis. Because of the radioresistance of some human cancers, particularly glioblastoma, we examined the use of a radio-gene therapy paradigm to sensitize cells to ionizing radiation. Based on the analysis of the structure-function of Ku70 and the crystal structure of Ku70/Ku80 heterodimer, we designed and identified a candidate dominant negative fragment involving an NH(2)-terminal deletion, and designated it as DNKu70. We generated this mutant construct, stably overexpressed it in Rat-1 cells, and showed that it has a dominant negative effect (i.e., DNKu70 overexpression results in decreased Ku-DNA end-binding activity, and increases radiosensitivity). We then constructed and generated recombinant replication-defective adenovirus, with DNKu70 controlled by the cytomegalovirus promoter, and infected human glioma U-87 MG cells and human colorectal tumor HCT-8 cells. We show that the infected cells significantly express DNKu70 and are greatly radiosensitized under both aerobic and hypoxic conditions. The functional ramification of DNKu70 was further shown in vivo: expression of DNKu70 inhibits radiation-induced DNA-PK catalytic subunit autophosphorylation and prolongs the persistence of gamma-H2AX foci. If radiation-resistant tumor cells could be sensitized by down-regulating the cellular level/activity of Ku/DNA-PK, this approach could be evaluated as an adjuvant to radiation therapy.

Integrating respiratory gating into a megavoltage cone-beam CT system.

We have previously described a low-dose megavoltage cone beam computed tomography (MV CBCT) system capable of producing projection image using one beam pulse. In this study, we report on its integration with respiratory gating for gated radiotherapy. The respiratory gating system tracks a reflective marker on the patient's abdomen midway between the xiphoid and umbilicus, and disables radiation delivery when the marker position is outside predefined thresholds. We investigate two strategies for acquiring gated scans. In the continuous rotation-gated acquisition, the linear accelerator (LINAC) is set to the fixed x-ray mode and the gantry makes a 5 min, 360 degree continuous rotation, during which the gating system turns the radiation beam on and off, resulting in projection images with an uneven distribution of projection angles (e.g., in 70 arcs each covering 2 degrees). In the gated rotation-continuous acquisition, the LINAC is set to the dynamic arc mode, which suspends the gantry rotation when the gating system inhibits the beam, leading to a slightly longer (6-7 min) scan time, but yielding projection images with more evenly distributed projection angles (e.g., approximately 0.8 degrees between two consecutive projection angles). We have tested both data acquisition schemes on stationary (a contrast detail and a thoracic) phantoms and protocol lung patients. For stationary phantoms, a separate motion phantom not visible in the images is used to trigger the RPM system. Frame rate is adjusted so that approximately 450 images (13 MU) are acquired for each scan and three-dimensional tomographic images reconstructed using a Feldkamp filtered backprojection algorithm. The gated rotation-continuous acquisition yield reconstructions free of breathing artifacts. The tumor in parenchymal lung and normal tissues are easily discernible and the boundary between the diaphragm and the lung sharply defined. Contrast-to-noise ratio (CNR) is not degraded relative to nongated scans of stationary phantoms. The continuous rotation-gated acquisition scan also yields tomographic images with discernible anatomic features; however, streak artifacts are observed and CNR is reduced by approximately a factor of 4. In conclusion, we have successfully developed a gated MV CBCT system to verify the patient positioning for gated radiotherapy.

Animal-specific positioning molds for registration of repeat imaging studies: comparative microPET imaging of F18-labeled fluoro-deoxyglucose and fluoro-misonidazole in rodent tumors.

INTRODUCTION: Comparative imaging of multiple radiotracers in the same animal can be invaluable in elucidating and validating their respective mechanisms of localization. Comparative imaging of PET tracers, particularly in small animals, is problematic, however: such tracers must be administered and imaged separately because simultaneously imaged positron emitters cannot be separated based on energy discrimination. OBJECTIVE: As part of our ongoing development of hypoxia imaging radiotracers, the intratumoral distributions of sequentially administered F18-fluoro-deoxyglucose (FDG) and the hypoxia tracer F18-fluoromisonidazole (FMiso) were compared in rats by registered microPET imaging with positioning of each animal in a custom-fabricated whole-body mold. METHODS: Nude rats with a hindlimb R3327-AT anaplastic rat prostate tumor xenograft and a hindlimb FaDu human squamous cell carcinoma (each up to 20 x 20 x 30 mm in size) were studied. Rapid-Foam (Soule Medical, Lutz, FL) was used to fabricate animal-specific molds for immobilization and reproducible positioning. Each rat was injected via the tail vein with approximately 33 MBq (900 microCi) of FDG and imaged in its mold at 1 h postinjection (pi) on the microPET. The next day, each rat was injected with approximately 22 MBq (600 microCi) of FMiso and positioned and imaged in its mold at approximately 2 h pi. Custom-manufactured germanium-68 rods (10 microCi each, 1 x 10 mm) were reproducibly positioned in the mold as fiduciary markers. RESULTS: The registered microPET images unambiguously demonstrated grossly similar though not identical distributions of FDG and FMiso in the tumors - a high-activity rim surrounding a lower-activity core. There were subtle but possibly significant differences in the intratumoral distributions of FDG and FMiso, however. These may not have been discerned without careful image registration. CONCLUSION: Animal-specific molds are inexpensive and straightforward to fabricate and use for registration (+/-1 to 2 mm) of sequential PET images and may aid image interpretation.

Reduction of organ motion in lung tumors with respiratory gating.

We evaluated the ability of a commercial respiratory gating system to assure the reproducibility of internal anatomy in respiration synchronized CT (RS-CT) scans. This passive system uses an infrared sensitive camera to track the motion of reflective markers mounted on the abdomen. Eighteen patients, nine with lung tumors and nine with liver tumors, were selected for evaluation of the Varian Real-Time Position Monitor respiratory gating system. Liver tumors were chosen as surrogate for lower lobe tumors. Each patient underwent at least two identical RS-CT scans, at end-inspiration (EI) or end-expiration (EE), to assess intra-fraction reproducibility. Twelve patients also underwent a free breathing scan and an opposed-respiration phase synchronized scan (EI if the two first were an EE and vice versa). On each CT, a physician contoured the liver, the kidneys, the spleen, and the diaphragms for the liver patients; and similarly, the lungs, the gross tumor volume (GTV), the trachea, the heart and the diaphragms for the lung patients. After registering the different CT images using bony anatomy, the changes of each structure between the respective data sets were quantified in terms of its volume, the displacement of its center of mass (COM), and an "index" coefficient of reproducibility. An analysis of the CT scans obtained at EI and EE phases yielded an average superior-inferior (SI) difference of the diaphragm position of 14.4 mm (range: 45.9-0.9). A similar analysis of CT scans acquired at the same breathing phase yielded 0.7 mm (range: 3.1-0, p=0.0001). Similar conclusions were derived in analysis of COM positions of the following structures: lungs, heart, lung's GTV, liver, spleen and kidneys. Evaluation of volume changes for lungs, liver, and spleen confirmed reproducibility of RS-CT while the "index" coefficient confirmed reproducibility of RS-CT of all organs. A commercial gating system using external markers for RS-CT significantly improves the positional reproducibility of thoracic and upper abdominal structures. This reproducible decrease in organ motion will allow a reduction of the margin of expansion facilitating increase in target dose beyond that allowed by conventional radiation treatments.

Intensity-modulated radiotherapy as the boost or salvage treatment of nasopharyngeal carcinoma: the appropriate parameters in the inverse planning and the effect of patient's anatomic factors on the planning results.

The current study demonstrates that the large increase in normal tissue penalty often degrades target dose uniformity without a concomitant large improvement in normal tissue dose, especially in anatomically unfavorable patients. The excessively large normal tissue penalties do not improve treatment plans for patients having unfavorable geometry.

Comparison of end normal inspiration and expiration for gated intensity modulated radiation therapy (IMRT) of lung cancer.

BACKGROUND AND PURPOSE: Gated delivery of radiation during part of the respiration cycle may improve the treatment of lung cancer with intensity modulated radiation therapy (IMRT). In terms of the respiration phase for gated treatment, normal end-expiration (EE) is more stable but normal end-inspiration (EI) increases lung volume. We compare the relative merit of using EI and EE in gated IMRT for sparing normal lung tissue. PATIENTS AND METHODS: Ten patients received EI and EE respiration-triggered CT scans in the treatment position. An IMRT plan for a prescription dose of 70 Gy was generated for each patient and at each respiration phase. The optimization constraints included target dose uniformity, less than 35% of the total lung receiving 20 Gy or more and maximum cord dose

Iodine-124-labeled iodo-azomycin-galactoside imaging of tumor hypoxia in mice with serial microPET scanning.

Tumor hypoxia, present in many human cancers, can lead to resistance to radiation and chemotherapy, is associated with a more aggressive tumor phenotype and is an independent prognostic factor of clinical outcome. It is therefore important to identify and localize tumor hypoxia in cancer patients. In the current study, serial microPET imaging was used to evaluate iodine-124-labeled iodo-azomycin-galactoside ((124)I-IAZG) (4.2-day physical half-life) as a hypoxia imaging agent in 17 MCa breast tumors and six FSaII fibrosarcomas implanted in mice. For comparison, another promising hypoxic-cell PET radiotracer, fluorine-18-labeled fluoro-misonidazole ((18)F-FMISO), was also imaged in the same tumor-bearing animals. Twelve animals were also imaged with (18)F-labeled fluoro-deoxyglucose ((18)F-FDG). In addition, histological examination was performed, and direct measurement of tumor oxygenation status carried out with the Oxylite probe system. Two size groups were used, relatively well-oxygenated tumors in the range of 80-180 mg were designated as small, and those >300 mg and highly hypoxic, as large. Based on the data from 11 MCa and six FSaII tumors, both (124)I-IAZG and (18)F-FMISO images showed high tracer uptake in the large tumors. In (18)F-FMISO images at 1, 3-4, and 6-8 h post-injection (p.i.), there was considerable whole-body background activity. In contrast, (124)I-IAZG imaging was optimal when performed at 24-48 h p.i., when the whole-body background had dissipated considerably. As a result, the (124)I-IAZG images at 24-48 h p.i. had higher tumor to whole-body activity contrast than the (18)F-FMISO images at 3-6 h p.i. Region-of-interest analysis was performed as a function of time p.i. and indicated a tumor uptake of 5-10% (of total-body activity) for FMISO at 3-6 h p.i., and of ~17% for IAZG at 48 h p.i. This was corroborated by biodistribution data in that the tumor-to-normal tissue (T/N, normal tissues of blood, heart, lung, liver, spleen, kidney, intestine, and muscle) activity ratios of IAZG at 24 h p.i. was 1.5-2 times higher than those of FMISO at 3 h p.i., with the exception of stomach. Statistical analysis indicated that these differences in T/N ratios were significant. The small tumors were visualized in the (18)F-FDG images, but not in the (124)I-IAZG or (18)F-FMISO images. This was perhaps due to the combined effect of a smaller tumor volume and a lower hypoxic fraction. Oxylite probe measurement indicated a lesser proportion of regions with pO(2)<2.5 mmHg in the small tumors (e.g., pO(2) was <2.5 mmHg in 28% and 67% of the data in small and large FSaII tumors, respectively), and the biodistribution data showed lower uptake of the tracers in the small tumors than in the large tumors. In the first study of its kind, using serial microPET imaging in conjunction with biodistribution analysis and direct probe measurements of local pO(2) to evaluate tumor hypoxia markers, we have provided data showing the potential of (124)I-IAZG for hypoxia imaging.

Evaluation of rapid dose map acquisition of a scanning liquid-filled ionization chamber electronic portal imaging device.

PURPOSE: We evaluated the performance of a new dosimetry module in the LC250 scanning liquid-filled ionization chamber (SLIC) electronic portal imaging device (EPID) for intensity-modulated radiotherapy (IMRT) verification. This module permits one to convert EPID readings to two-dimensional (2D) maps of IMRT dose rate in real time, and to integrate them over time to produce a profile of accumulated dose for treatment verification. METHODS AND MATERIALS: The EPID was calibrated using an iterative procedure, from which a lookup table for dose integration was generated and transferred to the image-acquisition hardware. To evaluate the EPID's integration capability, we investigated the linearity of imaging time (vs. monitor unit [MU]) and integrated dose (vs. planned dose) for static and IMRT fields, in both standard ( approximately 2.7 s/image) and fast ( approximately 1 s/image) synchronous acquisition modes (S- and F-modes). We also compared the EPID-measured profiles with that measured using film and ionization chamber, or calculated from the treatment planning system. For the EPID's patient dose verification capability, we compared the integrated central-axis (CAX) dose with the planned dose for 25 prostate IMRT fields. We also compared the measured relative profiles with the planned ones using a linear regression model, which returns an index sigma (root mean squared error) for the goodness of fit. We identified errors that are either associated with the timing of the EPID-start delay and end truncation, or with the integration process-detector memory effects (decrease in detector's sensitivity with time during the fast continuous acquisition) and beam hold-off effects (the withholding of linac beam pulses when multileaf collimator leaves are not in the correct positions). The CAX doses of static fields were corrected using the ratio of the irradiation time to the imaging time. A linear decay model was proposed to correct the detector memory effect. To investigate the beam hold-off effect, we verified the relative profiles of a five-field prostate IMRT plan for five different MU settings, and correlated the goodness of fit with the percent of beam hold-off. RESULTS: The imaging time is linearly proportional to the given MU with a slope of 0.250 MU/s (ideal slope is 0.250 MU/s) and a R(2) = 1.0. Although the R(2) of the linearity for the measured vs. planned dose is 1.0 for both modes, only the slopes for the S-mode are within 3% of unity. The slopes for the F-mode deviate from unity due to detector memory effects, and are accurately corrected using the linear decay model. The EPID measured profiles agree well (within 2.0%) with the planned dose and profiles for both modes. For the CAX dose of the 25 IMRT fields, the S-mode is within 2% of the planned dose, whereas the F-mode is off significantly (>3%) if not corrected for detector memory effects. For the relative profile verification, lower MU always produces higher sigma for the same mode. The F-mode is more accurate than the S-mode for the same MU; however, the improvement is not proportional to the difference in imaging speed. Analysis of the correlation of the goodness of fit with the percent of beam hold-off indicates that the accuracy of profile verification for the F-mode is predominantly determined by the beam hold-off effect for lower MU. CONCLUSION: The S-mode of LC250 combined with a large MU can be used for the pretreatment verification of IMRT beam delivery with a significant reduction of processing time and computer resources in comparison to off-line processing. Real-time verification during treatment requires the F-mode. Although the detector memory effects encountered in the F-mode can be compensated using the proposed linear decay model, sufficient accuracy for real-time verification requires a resolution of the beam hold-off problem.