Jenghwa Chang

Safety and Efficacy of Bevacizumab With Hypofractionated Stereotactic Irradiation for Recurrent Malignant Gliomas

PURPOSE Preclinical studies suggest that inhibition of vascular endothelial growth factor (VEGF) improves glioma response to radiotherapy. Bevacizumab, a monoclonal antibody against VEGF, has shown promise in recurrent gliomas, but the safety and efficacy of concurrent bevacizumab with brain irradiation has not been extensively studied. The objectives of this study were to determine the safety and activity of this combination in malignant gliomas. METHODS AND MATERIALS After prior treatment with standard radiation therapy patients with recurrent glioblastoma (GBM) and anaplastic gliomas (AG) received bevacizumab (10 mg/kg intravenous) every 2 weeks of 28-day cycles until tumor progression. Patients also received 30 Gy of hypofractionated stereotactic radiotherapy (HFSRT) in five fractions after the first cycle of bevacizumab. RESULTS Twenty-five patients (20 GBM, 5 AG; median age 56 years; median Karnofsky Performance Status 90) received a median of seven cycles of bevacizumab. One patient did not undergo HFSRT because overlap with prior radiotherapy would exceed the safe dose allowed to the optic chiasm. Three patients discontinued treatment because of Grade 3 central nervous system intratumoral hemorrhage, wound dehiscence, and bowel perforation. Other nonhematologic and hematologic toxicities were transient. No radiation necrosis was seen in these previously irradiated patients. For the GBM cohort, overall response rate was 50%, 6-month progression-free survival was 65%; median overall survival was 12.5 months, and 1-year survival was 54%. DISCUSSION Bevacizumab with HFSRT is safe and well tolerated. Radiographic responses, duration of disease control, and survival suggest that this regimen is active in recurrent malignant glioma.

Cone-beam CT with megavoltage beams and an amorphous silicon electronic portal imaging device: potential for verification of radiotherapy of lung cancer.

We investigate the potential of megavoltage (MV) cone-beam CT with an amorphous silicon electronic portal imaging device (EPID) as a tool for patient position verification and tumor/organ motion studies in radiation treatment of lung tumors. We acquire 25 to 200 projection images using a 22 x 29 cm EPID. The acquisition is automatic and requires 7 minutes for 100 projections; it can be synchronized with respiratory gating. From these images, volumetric reconstruction is accomplished with a filtered backprojection in the cone-beam geometry. Several important prereconstruction image corrections, such as detector sag, must be applied. Tests with a contrast phantom indicate that differences in electron density of 2% can be detected with 100 projections, 200 cGy total dose. The contrast-to-noise ratio improves as the number of projections is increased. With 50 projections (100 cGy), high contrast objects are visible, and as few as 25 projections yield images with discernible features. We identify a technique of acquiring projection images with conformal beam apertures, shaped by a multileaf collimator, to reduce the dose to surrounding normal tissue. Tests of this technique on an anthropomorphic phantom demonstrate that a gross tumor volume in the lung can be accurately localized in three dimensions with scans using 88 monitor units. As such, conformal megavoltage cone-beam CT can provide three-dimensional imaging of lung tumors and may be used, for example, in verifying respiratory gated treatments.

Relative profile and dose verification of intensity-modulated radiation therapy

PURPOSE To develop a quality assurance (QA) procedure to assess the intensity profile and dosimetry for intensity-modulated (IM) treatment fields using electronic portal imaging devices (EPIDs). METHODS AND MATERIALS A series of rapidly acquired (approximately 1/sec) portal images are summed and converted to dose. For relative intensity QA, the intended profile is subtracted point-by-point from the measured profile forming a series of error values. The standard deviation, sigma, of the errors, a measure of the goodness of the match, is minimized by applying a normalization and uniform scatter subtraction from the measured profile. For dose verification (dose to isocenter), an empirically determined phantom-correction factor is added to incorporate the effect of patient presence on EPID readings. Seventy prostate treatment fields were used in a phantom study to verify these approaches. Sensitivity was studied by creating artificial mismatches. RESULTS The average sigma for relative profile verification is 3.3% (percentage of average intended intensity) whereas artificial mismatches resulted in sigma values from 5% to 27%. The average isocentric dose calculated from EPID readings is 1.001 relative to the planned dose with a standard deviation of 0.018. CONCLUSIONS An EPID can be used for profile verification and absolute isocentric dose measurement for IM fields.

Hypofractionated Stereotactic Radiotherapy Using Intensity-Modulated Radiotherapy in Patients with One or Two Brain Metastases

Purpose: A small fraction of patients with 1–2 brain metastases will not be suitable candidates to either surgical resection or stereotactic radiosurgery (SRS) due to either their location or their size. The objective of this study was to determine the local control, survival, patterns of relapse and the incidence of brain injury following a course of hypofractionated stereotactic radiotherapy while avoiding upfront whole brain radiation therapy (WBRT) in this subgroup of patients. Methods: A Gill-Thomas removable head frame system was used for immobilization. Brain LAB software with dynamic multileaf collimator hardware was used to design and deliver an intensity-modulated radiation therapy treatment plan. A dose of 600 cGy was prescribed to the 100% isodose line that would encompass the lesion with a 3-mm margin. A total dose of 3,000 cGy was delivered in 5 fractions using 2 fractions per week. The patients were followed with neurological examination and serial MRI images done every 3 months following the procedure. Results: Twenty patients have been treated using this fractionation schedule since April 2004. The 1-year local control at the site of original disease is 70%. The complete response, partial response and stable disease at the last follow-up were 15, 30 and 45%, respectively. Two patients had local recurrence at the site of original disease, while 5 had evidence of leptomeningeal disease. Two additional patients developed new brain metastases, resulting in a 1-year brain relapse-free survival of 36% following this approach. The median overall survival was 8.5 months. Three patients (15%) developed steroid dependency lasting 3 months or longer following the procedure. Four patients (20%) needed WBRT as salvage following this approach. Conclusions: The preliminary results of hypofractionated SRS are comparable to both surgery and SRS data for solitary brain metastases in terms of local control and overall survival with acceptable morbidity in this cohort of unfavorable patients.

Developments in megavoltage cone beam CT with an amorphous silicon EPID: reduction of exposure and synchronization with respiratory gating.

We have studied the feasibility of a low-dose megavoltage cone beam computed tomography (MV CBCT) system for visualizing the gross tumor volume in respiratory gated radiation treatments of nonsmall-cell lung cancer. The system consists of a commercially available linear accelerator (LINAC), an amorphous silicon electronic portal imaging device, and a respiratory gating system. The gantry movement and beam delivery are controlled using dynamic beam delivery toolbox, a commercial software package for executing scripts to control the LINAC. A specially designed interface box synchronizes the LINAC, image acquisition electronics, and the respiratory gating system. Images are preprocessed to remove artifacts due to detector sag and LINAC output fluctuations. We report on the output, flatness, and symmetry of the images acquired using different imaging parameters. We also examine the quality of three-dimensional (3D) tomographic reconstruction with projection images of anthropomorphic thorax, contrast detail, and motion phantoms. The results show that, with the proper choice of imaging parameters, the flatness and symmetry are reasonably good with as low as three beam pulses per projection image. Resolution of 5% electron density differences is possible in a contrast detail phantom using 100 projections and 30 MU. Synchronization of image acquisition with simulated respiration also eliminated motion artifacts in a moving phantom, demonstrating the systems capability for imaging patients undergoing gated radiation therapy. The acquisition time is limited by the patients respiration (only one image per breathing cycle) and is under 10 min for a scan of 100 projections. In conclusion, we have developed a MV CBCT system using commercially available components to produce 3D reconstructions, with sufficient contrast resolution for localizing a simulated lung tumor, using a dose comparable to portal imaging.

Accuracy and feasibility of cone‐beam computed tomography for stereotactic radiosurgery setup

Image fusion, target localization, and setup accuracy of cone-beam computed tomography (CBCT) for stereotactic radiosurgery (SRS) were investigated in this study. A Rando head phantom rigidly attached to a stereotactic Brown-Roberts-Wells (BRW) frame was utilized to study the geometric accuracy of CBCT. Measurements of distances and angular separations between selected pairs of multiple radio-opaque targets embedded in the head phantom from a conventional simulation CT provided comparative data for geometric accuracy analysis. Localization accuracy of the CBCT scan was investigated from an analysis of BRW localization of four cylindrical objects (9 mm in diameter and 25 mm in length) independently computed from CBCT and conventional CT scans. Image fusion accuracy was quantitatively evaluated from BRW localization of multiple simulated targets from the CBCT and conventional CT scan. Finally, a CBCT setup procedure for stereotactic radiosurgery treatments was proposed and its accuracy was assessed using orthogonal target verification imaging. Our study showed that CBCT did not present any significant geometric distortions. Stereotactic coordinates of the four cylindrical objects as determined from the CBCT differed from those determined from the conventional CT on average by 0.30 mm with a standard deviation (SD) of 0.09 mm. The mean image registration accuracy of CBCT with conventional CT was 0.28 mm (SD = 0.10 mm). Setup uncertainty of our proposed CBCT setup procedure was on the same order as the conventional framed-based stereotactic systems reported in the literature (mean = 1.34 mm, SD = 0.33 mm). In conclusion, CBCT can be used to guide SRS treatment setup with accuracy comparable to the currently used frame-based stereotactic radiosurgery systems provided that intra-treatment patient motion is prevented.

Use of EPID for leaf position accuracy QA of dynamic multi‐leaf collimator (DMLC) treatment

We describe in this paper an alternative method for routine dynamic multi-leaf collimator (DMLC) quality assurance (QA) using an electronic portal imaging device (EPID). Currently, this QA is done at our institution by filming an intensity-modulated radiotherapy (IMRT) test field producing a pattern of five 1-mm bands 2 cm apart and performing a visual spot-check for leaf alignment, motion lags, sticking and any other mechanical problems. In this study, we used an amorphous silicon aS500 EPID and films contemporaneously for the DMLC QA to test the practicality and efficacy of EPID vis-à-vis film. The EPID image was transformed to an integrated dose map by first converting the reading to dose using a calibration curve, and then multiplying by the number of averaged frames. The EPID dose map was then back-projected to the central axis plane and was compared to the film measurements which were scanned and converted to dose using a film dosimetry system. We determined the full-width half-maximum (FWHM) of each band for both images, and evaluated the dose to the valley between two peaks. We also simulated mechanical problems by increasing the band gap to 1.5 mm for some leaf pairs. Our results show that EPID is as good as the film in resolving the band pattern of the IMRT test field. Although the resolution of the EPID is lower than that of the film (0.78 mm/pixel vs 0.36 mm/pixel for the film), it is high enough to faithfully reproduce the band pattern without significant distortion. The FWHM of the EPID is 2.84 mm, slightly higher than the 2.01 mm for the film. The lowest dose to the valley is significantly lower for the EPID (15.5% of the peak value) than for the film (28.6%), indicating that EPID is less energy independent. The simulated leaf problem can be spotted by visual inspection of both images; however, it is more difficult for the film without being scanned and contrast-enhanced. EPID images have the advantage of being already digital and their analysis can easily be automated to flag leaf pairs outside tolerance limits of set parameters such as FWHM, peak dose values, peak location, and distance between peaks. This automation is a new feature that will help preempt MLC motion interlocks and decrease machine downtime during actual IMRT treatment. We conclude that since EPID images can be acquired, analyzed and stored much more conveniently than film, EPID is a good alternative to film for routine DMLC QA.

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 patients 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.

Optimization of conformal thoracic radiotherapy using cone-beam CT imaging for treatment verification.

PURPOSE Megavoltage cone-beam computed tomography (MVCBCT) has been proposed for treatment verification in conformal radiotherapy. However, the doses required for such imaging may compromise the quality of the delivered dose distribution. The present paper explores the effect of cone-beam imaging on dose homogeneity and critical organ dose and the use of our new tool, adapted intensity-modulated radiation therapy (AIMRT). METHODS AND MATERIALS Three types of treatment plans were devised (3D-CRT [three-dimensional conformal radiotherapy], IMRT [intensity-modulated radiotherapy], and AIMRT) based on 4 patients with thoracic malignancies. MVCBCT fields were then integrated into the plans. The MVCBCT technique used 21 imaging portals at 10 degrees intervals. The MVCBCT apertures were shaped to conform to the planning target volume with a 6-mm margin. In a second set of plans, the field size was expanded by a further 2 cm. The unoptimized MVCBCT dose distribution was incorporated into the IMRT plan using AIMRT. RESULTS Normal-tissue complication probability with MVCBCT is acceptable for all plans at the 66.6 Gy level, but exceeds tolerance for both 3D-CRT alone and 3D-CRT with MVCBCT at higher doses. In contrast, the use of AIMRT planning with MVCBCT allowed safe dose escalation to 85 Gy. Expanding the MVCBCT aperture provided better anatomic visibility with an acceptable lung dose. The results using IMRT with MVCBCT fell between the values measured for 3D-CRT and AIMRT with MVCBCT. CONCLUSION The present study is the first to demonstrate that MVCBCT can be incorporated into 3D-CRT and IMRT planning with minimal effect on planning target volume homogeneity and dose to critical structures. This paves the way for highly conformal radiotherapy at greater doses delivered with increased confidence and safety.

An iterative EPID calibration procedure for dosimetric verification that considers the EPID scattering factor.

There has been an increasing interest in the application of electronic portal imaging devices (EPIDs) to dosimetric verification, particularly for intensity modulated radiotherapy. Although not water equivalent, the phantom scatter factor of an EPID, Spe, is generally assumed to be that of a full phantom, Sp, a slab phantom, Sps, or a mini phantom. This assumption may introduce errors in absolute dosimetry using EPIDs. A calibration procedure that iteratively updates Spe and the calibration curve (pixel value to dose rate) is presented. The EPID (Varian Portal Vision) is irradiated using a 20 x 20 cm2 field with different beam intensities. The initial guess of dose rates in the EPID is calculated from ionization chamber measurements in air, multiplied by Sp or Sps. The calibration curve is obtained by fitting EPID readings from pixels near the beam central axis and dose rates in EPID to a quadratic equation. The Spe is obtained from EPID measurements in 10 X 10 cm2 and 20 x 20 cm2 field and from the calibration curve, and is in turn used to adjust the dose rate measurements and hence the calibration curve. The above procedure is repeated until it converges. The final calibration curve is used to convert portal dose to dose in the slab phantom, using the calibrated Spe, or assuming Spe = Sp or Spe=Sps . The converted doses are then compared with the dose measured using an ionization chamber. We also apply this procedure to off-axis points and study its dependence on the energy spectrum. The hypothesis testing results (on the 95% significance level) indicate that systematic errors are introduced when assuming Spe = Sp or Spe=Sps and the dose calculated using Spe is more consistent with ionization chamber measurements. Differences between Spe and Sps are as large as 2% for large field sizes. The measured relative dose profile at dmax using the EPID agrees well with the measured profile at dmax of the isocentric plane using film in a polystyrene phantom with full buildup and full backup, for open and wedged fields, and for a broad range of field sizes of interest. The dependence of the EPID response on the energy spectrum is removed once the calibration is performed under the same conditions as the actual measurements.