Adding customized electron energy beams to TrueBeam linear accelerators.

PURPOSE: To better meet clinical needs and facilitate optimal treatment planning, we added two new electron energy beams (7 and 11 MeV) to two Varian TrueBeam linacs. METHODS: We worked with the vendor to create two additional customized electron energies without hardware modifications. For each beam, we set the bending magnet current and then optimized other beam-specific parameters to achieve depths of 50% ionization (I50 ) of 2.9 cm for 7 MeV and 4.2 cm for the 11 MeV beam with the 15 × 15 cm2 cone at 100 cm source-to-surface distance (SSD) by using an ionization chamber profiler (ICP) with a double-wedge (DW) phantom. Beams were steered and balanced to optimize symmetry with the ICP. After all parameters were set, full commissioning was done including measuring beam profiles, percent depth doses (PDDs), output factors (OFs) at standard, and extended SSDs. Measured data were compared between the two linacs and against the values calculated by our RayStation treatment planning system (TPS) following Medical Physics Practice Guideline 5.a (MPPG 5.a) guidelines. RESULTS: The I50 values initially determined with the ICP/DW agreed with those from a PDD-scanned in-water phantom within 0.2 mm for the 7 and 11 MeV on both linacs. Comparison of the beam characteristics from the two linacs indicated that flatness and symmetry agreed within 0.4%, and point-by-point differences in PDD were within 0.01% ± 0.3% for the 7 MeV and 0.01% ± 0.3% for the 11 MeV. The OF ratios between the two linacs were 1.000 ± 0.007 for the 7 MeV and 1.004 ± 0.007 for the 11 MeV. Agreement between TPS-calculated outputs and measurements were -0.1% ± 1.0% for the 7 MeV and 0.2% ± 0.8% for the 11 MeV. All other parameters met the MPPG 5.a's 3%/3-mm criteria. CONCLUSION: We were able to add two new beam energies with no hardware modifications. Tuning of the new beams was facilitated by the ICP/DW system allowing us to have the procedures done in a few hours and achieve highly consistent results across two linacs. PACS numbers: 87.55.Qr, 87.56.Fc.

Interplay effect on a 6-MV flattening-filter-free linear accelerator with high dose rate and fast multi-leaf collimator motion treating breast and lung phantoms.

PURPOSE: Using a new linear accelerator with high dose rate (800 MU/min), fast MLC motions (5.0 cm/s), fast gantry rotation (15 s/rotation), and 1 cm wide MLCs, we aimed to quantify the effects of complexity, arc number, and fractionation on interplay for breast and lung treatments under target motion. METHODS: To study lung interplay, eight VMAT plans (1-6 arcs) and four-nine-field sliding-window IMRT plans varying in complexity were created. For the breast plans, four-four-field sliding-window IMRT plans were created. Using the Halcyon 1.0 linear accelerator, each plan was delivered five times each under sinusoidal breathing motion to a phantom with 20 implanted MOSFET detectors; MOSFET dose (cGy), delivery time, and MU/cGy values were recorded. Maximum and mean dose deviations were calculated from MOSFET data. The number of MOSFETs with at least 19 of 20 detectors agreeing with their expected dose within 5% per fraction was calculated across 106 iterations to model dose deviation as function of fraction number for all plan variants. To put interplay plans into clinical context, additional IMRT and VMAT plans were created and delivered for the sites of head and neck, prostate, whole brain, breast, pelvis, and lung. Average modulation and interplay effect were compared to those from conventional linear accelerators, as reported from previous studies. RESULTS: The mean beam modulation for plans created for the Halcyon 1.0 linear accelerator was 2.9 MU/cGy (two- to four-field IMRT breast plans), 6.2 MU/cGy (at least five-field IMRT), and 3.6 MU/cGy (four-arc VMAT). To achieve treatment plan objectives, Halcyon 1.0 VMAT plans require more arcs and modulation than VMAT on conventional linear accelerators. Maximum and mean dose deviations increased with increasing plan complexity under tumor motion for breast and lung treatments. Concerning VMAT plans under motion, maximum, and mean dose deviations were higher for one arc than for two arcs regardless of plan complexity. For plan variants with maximum dose deviations greater than 3.7%, dose deviation as a function of fraction number was protracted. CONCLUSION: For treatments on the Halcyon 1.0 linear accelerator, the convergence of dose deviation with fraction number happened more slowly than reported for conventional linear accelerators. However, if plan complexity is reduced for IMRT and if tumor motion is less than ~10-mm, interplay is greatly reduced. To minimize dose deviations across multiple fractions for dynamic targets, we recommend limiting treatment plan complexity and avoiding one-arc VMAT on the Halcyon 1.0 linear accelerator when interplay is a concern.

3-Dimensional magnetic resonance spectroscopic imaging at 3 Tesla for early response assessment of glioblastoma patients during external beam radiation therapy.

PURPOSE: To evaluate the utility of 3-dimensional magnetic resonance (3D-MR) proton spectroscopic imaging for treatment planning and its implications for early response assessment in glioblastoma multiforme. METHODS AND MATERIALS: Eighteen patients with newly diagnosed, histologically confirmed glioblastoma had 3D-MR proton spectroscopic imaging (MRSI) along with T2 and T1 gadolinium-enhanced MR images at simulation and at boost treatment planning after 17 to 20 fractions of radiation therapy. All patients received standard radiation therapy (RT) with concurrent temozolomide followed by adjuvant temozolomide. Imaging for response assessment consisted of MR scans every 2 months. Progression-free survival was defined by the criteria of MacDonald et al. MRSI images obtained at initial simulation were analyzed for choline/N-acetylaspartate ratios (Cho/NAA) on a voxel-by-voxel basis with abnormal activity defined as Cho/NAA ≥2. These images were compared on anatomically matched MRSI data collected after 3 weeks of RT. Changes in Cho/NAA between pretherapy and third-week RT scans were tested using Wilcoxon matched-pairs signed rank tests and correlated with progression-free survival, radiation dose and location of recurrence using Cox proportional hazards regression. RESULTS: After a median follow-up time of 8.6 months, 50% of patients had experienced progression based on imaging. Patients with a decreased or stable mean or median Cho/NAA values had less risk of progression (P<.01). Patients with an increase in mean or median Cho/NAA values at the third-week RT scan had a significantly greater chance of early progression (P<.01). An increased Cho/NAA at the third-week MRSI scan carried a hazard ratio of 2.72 (95% confidence interval, 1.10-6.71; P=.03). Most patients received the prescription dose of RT to the Cho/NAA ≥2 volume, where recurrence most often occurred. CONCLUSION: Change in mean and median Cho/NAA detected at 3 weeks was a significant predictor of early progression. The potential impact for risk-adaptive therapy based on early spectroscopic findings is suggested.

Magnetic resonance imaging (MRI) markers for MRI-guided high-dose-rate brachytherapy: novel marker-flange for cervical cancer and marker catheters for prostate cancer.

PURPOSE: To present a novel marker-flange, addressing source-reconstruction uncertainties due to the artifacts of a titanium intracavitary applicator used for magnetic resonance imaging (MRI)-guided high-dose-rate (HDR) brachytherapy (BT); and to evaluate 7 different MRI marker agents used for interstitial prostate BT and intracavitary gynecologic HDR BT when treatment plans are guided by MRI. METHODS AND MATERIALS: Seven MRI marker agents were analyzed: saline solution, Conray-60, copper sulfate (CuSO4) (1.5 g/L), liquid vitamin E, fish oil, 1% agarose gel (1 g agarose powder per 100 mL distilled water), and a cobalt-chloride complex contrast (C4) (CoCl2/glycine = 4:1). A plastic, ring-shaped marker-flange was designed and tested on both titanium and plastic applicators. Three separate phantoms were designed to test the marker-flange, interstitial catheters for prostate BT, and intracavitary catheters for gynecologic HDR BT. T1- and T2-weighted MRI were analyzed for all markers in each phantom and quantified as percentages compared with a 3% agarose gel background. The geometric accuracy of the MR signal for the marker-flange was measured using an MRI-CT fusion. RESULTS: The CuSO4 and C4 markers on T1-weighted MRI and saline on T2-weighted MRI showed the highest signals. The marker-flange showed hyper-signals of >500% with CuSO4 and C4 on T1-weighted MRI and of >400% with saline on T2-weighted MRI on titanium applicators. On T1-weighted MRI, the MRI signal inaccuracies of marker-flanges were measured <2 mm, regardless of marker agents, and that of CuSO4 was 0.42 ± 0.14 mm. CONCLUSION: The use of interstitial/intracavitary markers for MRI-guided prostate/gynecologic BT was observed to be feasible, providing accurate source pathway reconstruction. The novel marker-flange can produce extremely intense, accurate signals, demonstrating its feasibility for gynecologic HDR BT.

Image-based biomarkers in clinical practice.

The growth of functional and metabolically informative imaging is eclipsing anatomic imaging alone in clinical practice. The recognition that magnetic resonance (MR) and positron emission tomography (PET)-based treatment planning and response assessment are essential components of clinical practice and furthermore offer the potential of quantitative analysis being important. Extracting the greatest benefit from these imaging techniques will require refining the best combinations of multimodality imaging through well-designed clinical trials that use robust image-analysis tools and require substantial computer based infrastructure. Through these changes and enhancements, image-based biomarkers will enhance clinical decision making and accelerate the progress that is made through clinical trial research.

Evaluation of artifacts and distortions of titanium applicators on 3.0-Tesla MRI: feasibility of titanium applicators in MRI-guided brachytherapy for gynecological cancer.

PURPOSE: The aim of this study was to characterize the levels of artifacts and distortions of titanium applicators on 3.0-Tesla magnetic resonance imaging (MRI). METHODS AND MATERIALS: Fletcher-Suit-Delclos-style tandem and ovoids (T&O) and tandem and ring applicator (T&R) were examined. The quality assurance (QA) phantoms for each applicator were designed and filled with copper sulphate solution (1.5 g/l). The artifacts were quantified with the registration of corresponding computed tomography (CT) images. A favorable MR sequence was searched in terms of artifacts. Using the sequence, the artifacts were determined. The geometric distortions induced by the applicators were quantified through each registration of CT and MRI without applicators. The artifacts of T&O were also evaluated on in vivo MRI datasets of 5 patients. RESULTS: T1-weighted MRI with 1-mm slice thickness was found as a favorable MR sequence. Applying the sequence, the artifacts at the tandem tip of T&O and T&R were determined as 1.5 ± 0.5 mm in a superior direction in phantom studies. In the ovoids of T&O, we found artifacts less than 1.5 ± 0.5 mm. The artifacts of a T&O tandem in vivo were found as less than 2.6 ± 1.3 mm on T1-weighted MRI, whereas less than 6.9 ± 3.4 mm on T2-weighted MRI. No more than 1.2 ± 0.6 mm (3.0 ± 1.5 mm) of distortions, due to a titanium applicator, were measured on T1-weighted MRI (T2-). CONCLUSION: In 3.0-Tesla MRI, we found the artifact widths at the tip of tandem were less than 1.5 ± 0.5 mm for both T&O and T&R when using T1-weighted MRI in phantom studies. However, exclusive 3.0-Tesla MRI-guided brachytherapy planning with a titanium applicator should be cautiously implemented.

Therapeutic strategy for acute spinal cord contusion injury: cell elimination combined with microsurgical intervention.

BACKGROUND: No cure is available for human spinal cord injury. Cell elimination by localized radiation therapy that is timed within 2-3 weeks postinjury can facilitate repair of structure and function in transected rat spinal cord. In pilot studies in contusion spinal cord injury, a model similar to crush/fracture injury in human, we did not observe the expected beneficial effects of radiation therapy. Long forgotten data show that in contusion/crush injury, fluid accumulation from hemorrhage is critical. Alfred Reginald Allen observed that the most devastating sequelae in contusive injury are secondary to fluid accumulation which could be alleviated by surgical intervention, midline slits (myelotomy) at the lesion site. METHODS AND FINDINGS: Here, we tested whether release of fluid buildup by microsurgery (partial myelotomy) would affect the structural outcome of radiation therapy in the severely contused rat spinal cord. Surgical intervention alone significantly enhanced tissue and functional preservation in the contused cord, thus confirming Allen's observations. Combining partial myelotomy with radiation therapy that is specifically timed postinjury elicited substantial beneficial therapeutic outcome; it led to significant increase in tissue repair/preservation compared with the group that received surgical intervention only, as determined by histology and in vivo MRI. Altogether, the combined treatments led to a 1.8 fold increase in tissue repair/preservation as compared with the contused group. CONCLUSIONS: The data suggest that a clinical protocol could be developed to treat acute human spinal cord injury through conventional clinical procedures, a combination of microsurgical manipulation and radiation therapy. These also suggest it is imperative to first prevent the secondary damage caused by fluid accumulation for a cure to be possible.

Preclinical evaluation of tumor microvascular response to a novel antiangiogenic/antitumor agent RO0281501 by dynamic contrast-enhanced MRI at 1.5 T.

Inhibition of tumor angiogenesis is a promising approach in cancer treatment. The purpose of this study was to evaluate the vascular response of human lung tumor xenografts in vivo to RO0281501, an inhibitor of tyrosine kinase receptors, including vascular endothelial growth factor receptor 2, fibroblast growth factor receptor, and platelet-derived growth factor receptor, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Human non-small cell lung carcinoma (H460a) xenografts grown s.c. in athymic nu/nu mice were treated p.o. with the antiangiogenic agent RO0281501. Treatment-induced changes in tumor volume, epiphyseal growth plate thickness, and microvessel density assessed by CD31 immunohistochemistry were analyzed. Tumor vascular permeability and perfusion were measured in tumors using DCE-MRI with gadopentetate dimeglumine on a 1.5 T clinical scanner to assess vascular function. Treatment with RO0281501 resulted in significant growth retardation of H460a tumors. RO0281501-treated tumors showed histologic evidence of growth plate thickening and relatively lower microvessel density compared with the controls. Regarding DCE-MRI variables, the initial slope of contrast uptake and Ak(ep) were significantly decreased on day 7 of treatment. RO0281501 is a novel antiangiogenic/antitumor agent, which is active in the H460a xenograft model. Its effects on tumor vasculature can be monitored and assessed by DCE-MRI on a 1.5 T human MR scanner with clinically available gadopentetate dimeglumine contrast, which will facilitate clinical trials with this or similar agents.

Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by 1H-decoupled-31P magnetic resonance spectroscopy.

PURPOSE: Attempts to selectively initiate tumor cell death through inducible apoptotic pathways are increasingly being exploited as a potential anticancer strategy. Inhibition of NAD+ synthesis by a novel agent FK866 has been recently reported to induce apoptosis in human leukemia, hepatocarcinoma cells in vitro, and various types of tumor xenografts in vivo. In the present study, we used 1H-decoupled phosphorus (31P) magnetic resonance spectroscopy (MRS) to examine the metabolic changes associated with FK866 induced tumor cell death in a mouse mammary carcinoma. EXPERIMENTAL DESIGN: Induction of apoptosis in FK866-treated tumors was confirmed by histology and cytofluorometric analysis. FK866-induced changes in mammary carcinoma tumor metabolism in vivo were investigated using 1H-decoupled 31P MRS. To discern further the changes in metabolic profiles of tumors observed in vivo, high-resolution in vitro 1H-decoupled 31P MRS studies were carried out with perchloric acid extracts of mammary carcinoma tumors excised after similar treatments. In addition, the effects of FK866 on mammary carcinoma tumor growth and radiation sensitivity were studied. RESULTS: Treatment with FK866 induced a tumor growth delay and enhanced radiation sensitivity in mammary carcinoma tumors that was associated with significant increases in the 31P MR signal in the phosphomonoester region and a decrease in NAD+ levels, pH, and bioenergetic status. The 31P MRS of perchloric acid extracts of treated tumors identified the large unresolved signal in the phosphomonoester region as the resultant of resonances originating from intermediates of tumor glycolysis and guanylate synthesis in addition to alterations in pyridine nucleotide pools and phospholipid metabolism. CONCLUSION: The present results suggest that FK866 interferes with multiple biochemical pathways that contribute to the increased cell death (apoptosis) and subsequent radiation sensitivity observed in the mammary carcinoma that could be serially monitored by 31P MRS.

Correlation of proton MR spectroscopic imaging with gleason score based on step-section pathologic analysis after radical prostatectomy.

PURPOSE: To determine whether hydrogen 1 magnetic resonance (MR) spectroscopic imaging can be used to predict aggressiveness of prostate cancer. MATERIALS AND METHODS: All patients gave informed consent according to an institutionally approved research protocol. A total of 123 patients (median age, 58 years; age range, 40-74 years) who underwent endorectal MR imaging and MR spectroscopic imaging between January 2000 and December 2002 were included. MR imaging and spectroscopy were performed by using combined pelvic phased-array and endorectal probe. Water and lipids were suppressed, and phase-encoded data were acquired with 6.2-mm resolution. Voxels in the peripheral zone were considered suspicious for cancer if (Cho + Cr)/Cit was at least two standard deviations above the normal level, where Cho represents choline-containing compounds, Cr represents creatine and phosphocreatine, and Cit represents citrate. Correlation between metabolite ratio and four Gleason score groups identified at step-section pathologic evaluation (3 + 3, 3 + 4, 4 + 3, and > or =4 + 4) was assessed with generalized estimating equations. RESULTS: Data from 94 patients were included. Pathologic evaluation was used to identify 239 lesions. Overall sensitivity of MR spectroscopic imaging was 56% for tumor detection, increasing from 44% in lesions with Gleason score of 3 + 3 to 89% in lesions with Gleason score greater than or equal to 4 + 4. There was a trend toward increasing (Cho + Cr)/Cit with increasing Gleason score in lesions identified correctly with MR spectroscopic imaging. Tumor volume assessed with MR spectroscopic imaging increased with increasing Gleason score. CONCLUSION: MR spectroscopic imaging measurement of prostate tumor (Cho + Cr)/Cit and tumor volume correlate with pathologic Gleason score. There is overlap between MR spectroscopic imaging parameters at various Gleason score levels, which may reflect methodologic and physiologic variations. MR spectroscopic imaging has potential in noninvasive assessment of prostate cancer aggressiveness.

In vivo tumor lactate relaxation measurements by selective multiple-quantum-coherence (Sel-MQC) transfer.

The frequency-selective multiple-quantum-coherence (Sel-MQC) lactate (Lac) filter offers complete lipid and water suppression in a single scan for robust in vivo detection of tumor Lac, even in the presence of abundant lipids. Conversion of the detected signal into accurate tissue concentrations of Lac requires knowledge of in vivo Lac T1 and T2 relaxation times. This work reports modifications to the Sel-MQC pulse sequence, T1- and T2-Sel-MQC, that facilitate relaxation measurements of Lac. The T1-Sel-MQC sequence combines an inversion prepulse with the Sel-MQC filter. The T2-Sel-MQC sequence incorporates a CH3-selective 180 degrees pulse during the MQ preparation period to overcome the J-modulation effects and allow the insertion of variable echo delays. The performance of these sequences was evaluated with the use of phantoms and subcutaneous murine tumor models in vivo. The present approach will allow investigators to correct for the relaxation-induced Lac signal loss in Sel-MQC experiments for the quantitative mapping of in vivo tumor Lac distribution.

Chronic prostatitis: MR imaging and 1H MR spectroscopic imaging findings--initial observations.

PURPOSE: To determine whether chronic prostatitis affects three-dimensional proton magnetic resonance (MR) spectroscopic imaging in evaluation of disease in the peripheral zone. MATERIALS AND METHODS: Combined MR imaging and three-dimensional MR spectroscopic imaging data were examined retrospectively in 12 patients with radical prostatectomy specimens that contained regions of chronic prostatitis larger than 6 mm in the peripheral zone. The 6-mm restriction was based on MR spectroscopic imaging spatial resolution of 6.25 mm. Transverse T2-weighted MR images were reviewed for changes in signal intensity (SI): normal, suspicious for cancer (nodular focal low SI), or indeterminate (focal low SI that was not nodular or contour deforming or diffuse low SI). At MR spectroscopic imaging, proton spectra were considered suspicious for cancer if the ratio of choline plus creatine to citrate was more than 2 SDs above normal mean peripheral zone values. RESULTS: In the 12 patients, mean pretreatment prostate-specific antigen level was 5.77 +/- 2.07 (SD), and median biopsy Gleason score for the gland was 6. At MR imaging in the area of histopathologically confirmed chronic prostatitis, seven of 12 patients had focal low SI that was not nodular (contour deforming) over a region in and around the pathologically defined focus of chronic prostatitis. MR imaging in one patient showed diffuse low SI that correlated with a diffuse area of chronic prostatitis at pathologic examination. MR imaging in another patient showed nodular focal low SI that was suspicious for cancer and corresponded to a focus of chronic prostatitis at pathologic examination. The remaining three patients had no MR imaging abnormality in the region of chronic prostatitis. In the pathologically identified regions of chronic prostatitis, MR spectroscopic imaging data in nine of 12 patients demonstrated elevated choline peak and reduced or no citrate, findings that mimic those of cancer. In two patients, the spectra were normal, and in the remaining patient, the spectra were nondiagnostic. CONCLUSION: At MR spectroscopic imaging, pathologically confirmed chronic prostatitis may demonstrate metabolic abnormality that leads to false-positive diagnosis of cancer. The most common MR imaging finding in chronic prostatitis was focal low SI that was not specific for cancer. In one patient, the MR imaging diagnosis of cancer could not be excluded.

Transition zone prostate cancer: metabolic characteristics at 1H MR spectroscopic imaging--initial results.

PURPOSE: To determine whether cancers of the prostate transition zone (TZ) possess a unique metabolic pattern by which they may be identified at proton magnetic resonance (MR) spectroscopic imaging. MATERIALS AND METHODS: Findings in 40 patients who underwent combined endorectal MR imaging and hydrogen 1 MR spectroscopic imaging before radical prostatectomy and who had TZ tumor identified subsequently at step-section pathologic analysis were retrospectively reviewed. Within this population, a subset of 16 patients whose TZ tumor had a largest diameter of 1 cm or greater and was included in the MR spectroscopic imaging excitation volume was identified. In these 16 patients, the ratios of choline-containing compounds (Cho) and creatine/phosphocreatine (Cr) to citrate (Cit) (ie, [Cho + Cr]/Cit), Cho/Cr, and Cho/Cit were compared in tumor and control tissues. The presence of only Cho and the absence of all metabolites were also assessed. RESULTS: The mean values of (Cho + Cr)/Cit, Cho/Cr, and Cho/Cit were different between TZ cancer and control tissues (P =.001, P =.003, and P =.001, respectively; Wilcoxon signed rank test). Nine (56%) of 16 patients had at least one tumor voxel in which Cho comprised the only detectable peak, while no control voxels showed only Cho (P =.008, McNemar test). The percentage of voxels in which no metabolites were detected did not differ between tumor and control tissues (P =.134, McNemar test). CONCLUSION: TZ cancer has a metabolic profile that is different from that of benign TZ tissue; however, the broad range of metabolite ratios observed in TZ cancer precludes the use of a single ratio to differentiate TZ cancer from benign TZ tissue.