Jerry Markman

A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: initial results☆

OBJECTIVES In a prospective clinical study, we tested the hypothesis that sparing the parotid glands may result in significant objective and subjective improvement of xerostomia in patients with head-and-neck cancers. The functional outcome 6 months after the completion of radiation therapy is presented. METHODS AND MATERIALS From February 1997 to February 1999, 41 patients with head-and-neck cancers were enrolled in a prospective salivary function study. Inverse-planning intensity-modulated radiation therapy (IMRT) was used to treat 27 patients, and forward-planning three-dimensional radiation therapy in 14. To avoid potential bias in data interpretation, only patients whose submandibular glands received greater than 50 Gy were eligible. Attempts were made to spare the superficial lobe of the parotid glands to avoid underdosing tumor targets in the parapharyngeal space; however, the entire parotid volume was used to compute dose-volume histograms (DVHs) for this analysis. DVHs were computed for each gland separately. Parotid function was assessed objectively by measuring stimulated and unstimulated saliva flow before and 6 months after the completion of radiation therapy. Measurements were converted to flow rate (mL/min) and normalized relative to that before treatment. The corresponding quality-of-life (QOL) outcome was assessed by five questions regarding the patients oral discomfort and eating/speaking problems. RESULTS We observed a correlation between parotid mean dose and the fractional reduction of stimulated saliva output at 6 months after the completion of radiation therapy. We further examined whether the functional outcome could be modeled as a function of dose. Two models were found to describe the dose-response data well. The first model assumed that each parotid gland is comprised of multiple independent parallel functional subunits (corresponding to computed tomography voxels) and that each gland contributes equally to overall flow, and that saliva output decreases exponentially as a quadratic function of irradiation dose to each voxel. The second approach uses the equivalent uniform dose (EUD) metrics, which assumes loss of salivary function with increase in EUD for each parotid gland independently. The analysis suggested that the mean dose to each parotid gland is a reasonable indicator for the functional outcome of each gland. The corresponding exponential coefficient was 0.0428/Gy (95% confidence interval: 0.01, 0.09). The QOL questions on eating/speaking function were significantly correlated with stimulated and unstimulated saliva flow at 6 months. In a multivariate analysis, a toxicity score derived from the model based on radiation dose to the parotid gland was found to be the sole significant predictive factor for xerostomia. Neither radiation technique (IMRT vs. non-IMRT) nor chemotherapy (yes or no) independently influenced the functional outcome of the salivary glands. CONCLUSION Sparing of the parotid glands translates into objective and subjective improvement of both xerostomia and QOL scores in patients with head-and-neck cancers receiving radiation therapy. Modeling results suggest an exponential relationship between saliva flow reduction and mean parotid dose for each gland. We found that the stimulated saliva flow at 6 months after treatment is reduced exponentially, for each gland independently, at a rate of approximately 4% per Gy of mean parotid dose.

Evaluation of polymer gels and MRI as a 3-D dosimeter for intensity-modulated radiation therapy.

BANG gel (MGS Research, Inc., Guilford, CT) has been evaluated for measuring intensity-modulated radiation therapy (IMRT) dose distributions. Treatment plans with target doses of 1500 cGy were generated by the Peacock IMRT system (NOMOS Corp., Sewickley, PA) using test target volumes. The gels were enclosed in 13 cm outer diameter cylindrical glass vessels. Dose calibration was conducted using seven smaller (4 cm diameter) cylindrical glass vessels irradiated to 0-1800 cGy in 300 cGy increments. Three-dimensional maps of the proton relaxation rate R2 were obtained using a 1.5 T magnetic resonance imaging (MRI) system (Siemens Medical Systems, Erlangen, Germany) and correlated with dose. A Hahn spin echo sequence was used with TR = 3 s, TE = 20 and 100 ms, NEX = 1, using 1 x 1 x 3 mm3 voxels. The MRI measurements were repeated weekly to identify the gel-aging characteristics. Ionization chamber, thermoluminescent dosimetry (TLD), and film dosimetry measurements of the IMRT dose distributions were obtained to compare against the gel results. The other dosimeters were used in a phantom with the same external cross-section as the gel phantom. The irradiated R2 values of the large vessels did not precisely track the smaller vessels, so the ionization chamber measurements were used to normalize the gel dose distributions. The point-to-point standard deviation of the gel dose measurements was 7.0 cGy. When compared with the ionization chamber measurements averaged over the chamber volume, 1% agreement was obtained. Comparisons against radiographic film dose distribution measurements and the treatment planning dose distribution calculation were used to determine the spatial localization accuracy of the gel and MRI. Spatial localization was better than 2 mm, and the dose was accurately determined by the gel both within and outside the target. The TLD chips were placed throughout the phantom to determine gel measurement precision in high- and low-dose regions. A multidimensional dose comparison tool that simultaneously examines the dose-difference and distance-to-agreement was used to evaluate the gel in both low-and high-dose gradient regions. When 3% and 3 mm criteria were used for the comparisons, more than 90% of the TLD measurements agreed with the gel, with the worst of 309 TLD chip measurements disagreeing by 40% of the criteria. All four MRI measurement session gel-measured dose distributions were compared to evaluate the time behavior of the gel. The low-dose regions were evaluated by comparison with TLD measurements at selected points, while high-dose regions were evaluated by directly comparing measured dose distributions. Tests using the multidimensional comparison tool showed detectable degradation beyond one week postirradiation, but all low-dose measurements passed relative to the test criteria and the dose distributions showed few regions that failed.

Validation of a precision radiochromic film dosimetry system for quantitative two‐dimensional imaging of acute exposure dose distributions

We present an evaluation of the precision and accuracy of image-based radiochromic film (RCF) dosimetry performed using a commercial RCF product (Gafchromic MD-55-2, Nuclear Associates, Inc.) and a commercial high-spatial resolution (100 microm pixel size) He-Ne scanning-laser film-digitizer (Personal Densitometer, Molecular Dynamics, Inc.) as an optical density (OD) imaging system. The precision and accuracy of this dosimetry system are evaluated by performing RCF imaging dosimetry in well characterized conformal external beam and brachytherapy high dose-rate (HDR) radiation fields. Benchmarking of image-based RCF dosimetry is necessary due to many potential errors inherent to RCF dosimetry including: a temperature-dependent time evolution of RCF dose response; nonuniform response of RCF; and optical-polarization artifacts. In addition, laser-densitometer imaging artifacts can produce systematic OD measurement errors as large as 35% in the presence of high OD gradients. We present a RCF exposure and readout protocol that was developed for the accurate dosimetry of high dose rate (HDR) radiation sources. This protocol follows and expands upon the guidelines set forth by the American Association of Physicists in Medicine (AAPM) Task Group 55 report. Particular attention is focused on the OD imaging system, a scanning-laser film digitizer, modified to eliminate OD artifacts that were not addressed in the AAPM Task Group 55 report. RCF precision using this technique was evaluated with films given uniform 6 MV x-ray doses between 1 and 200 Gy. RCF absolute dose accuracy using this technique was evaluated by comparing RCF measurements to small volume ionization chamber measurements for conformal external-beam sources and an experimentally validated Monte Carlo photon-transport simulation code for a 192Ir brachytherapy source. Pixel-to-pixel standard deviations of uniformly irradiated films were less than 1% for doses between 10 and 150 Gy; between 1% and 5% for lower doses down to 1 Gy and 1% and 1.5% for higher doses up to 200 Gy. Pixel averaging to form 200-800 microm pixels reduces these standard deviations by a factor of 2 to 5. Comparisons of absolute dose show agreement within 1.5%-4% of dose benchmarks, consistent with a highly accurate dosimeter limited by its observed precision and the precision of the dose standards to which it is compared. These results provide a comprehensive benchmarking of RCF, enabling its use in the commissioning of novel HDR therapy sources.

Characterization of a commercial multileaf collimator used for intensity modulated radiation therapy.

The characteristics of a commercial multileaf collimator (MLC) to deliver static and dynamic multileaf collimation (SMLC and DMLC, respectively) were investigated to determine their influence on intensity modulated radiation therapy (IMRT) treatment planning and quality assurance. The influence of MLC leaf positioning accuracy on sequentially abutted SMLC fields was measured by creating abutting fields with selected gaps and overlaps. These data were also used to measure static leaf positioning precision. The characteristics of high leaf-velocity DMLC delivery were measured with constant velocity leaf sequences starting with an open field and closing a single leaf bank. A range of 1-72 monitor units (MU) was used providing a range of leaf velocities. The field abutment measurements yielded dose errors (as a percentage of the open field max dose) of 16.7+/-0.7% mm(-1) and 12.8+/-0.7% mm(-1) for 6 MV and 18 MV photon beams, respectively. The MLC leaf positioning precision was 0.080+/-0.018 mm (single standard deviation) highlighting the excellent delivery hardware tolerances for the tested beam delivery geometry. The high leaf-velocity DMLC measurements showed delivery artifacts when the leaf sequence and selected monitor units caused the linear accelerator to move the leaves at their maximum velocity while modulating the accelerator dose rate to deliver the desired leaf and MU sequence (termed leaf-velocity limited delivery). According to the vendor, a unique feature to their linear accelerator and MLC is that the dose rate is reduced to provide the correct cm MU(-1) leaf velocity when the delivery is leaf-velocity limited. However, it was found that the system delivered roughly 1 MU per pulse when the delivery was leaf-velocity limited causing dose profiles to exhibit discrete steps rather than a smooth dose gradient. The root mean square difference between the steps and desired linear gradient was less than 3% when more than 4 MU were used. The average dose per MU was greater and less than desired for closing and opening leaf patterns, respectively, when the delivery was leaf-velocity limited. The results indicated that the dose delivery artifacts should be minor for most clinical cases, but limit the assumption of dose linearity when significantly reducing the delivered dose for dosimeter characterization studies or QA measurements.

Applicator-guided intensity-modulated radiation therapy

PURPOSE We are introducing a novel method for delivering highly conformal dose distributions to cervical cancer tumors using external beam intensity-modulated radiation therapy. The method, termed applicator-guided intensity-modulated radiation therapy (AGIMRT), will use an applicator substitute placed in the vagina and uterus to provide spatial registration and immobilization of the gynecologic organs. The main reason for the applicator substitute will be to localize the fornices, cervix, and uterus with the expectation that the other nearby organs will also be reproducibly positioned with respect to the applicator substitute. Intensity-modulated radiation therapy (IMRT) dose distributions will be used as a substitute for high-dose-rate intracavitary brachytherapy procedures. The flexibility of IMRT will enable customized dose distributions that have the potential to reduce complications and improve local control, especially for locally advanced disease. METHODS AND MATERIALS To test the advantages of IMRT over intracavitary brachytherapy, volumetric scans of three cervical cancer patients were obtained with implanted CT-compatible applicators. IMRT dose distribution simulations using tomotherapy, were compared against intracavitary brachytherapy using cesium tubes to investigate the dosimetric differences of the two modalities. Because these tumor volumes do not image well on CT, the target volumes were defined as the isodose surface containing the traditional point A, defined as 2 cm superior to the vaginal fornices and 2 cm lateral to the intrauterine canal. One patient had a uterus that wrapped superior and anterior to the bladder. For this case, the cervix and uterus were selected as the target volume. To determine the potential for using an applicator substitute to localize internal organs, the posterior bladder and anterior rectal surfaces were localized relative to the colpostats. Comparisons of the colpostat-localized surfaces were conducted for two scan studies for 3 patients. RESULTS The IMRT distributions covered the point-A isodose surfaces while reducing doses to the bladder and rectum. Brachytherapy showed extensive underdose regions in the target volume for the wrapped-around target. Spatial positioning was better than 0.7 and 1.3 cm in the rectum and bladder, respectively, indicating the potential that an applicator substitute may be able to localize these structures. CONCLUSIONS AGIMRT has the potential for improving critical structure avoidance while maintaining highly reproducible and accurate internal organ registration found with brachytherapy.

ON THE VALIDITY OF THE SUPERPOSITION PRINCIPLE IN DOSE CALCULATIONS FOR INTRACAVITARY IMPLANTS WITH SHIELDED VAGINAL COLPOSTATS

Intracavitary vaginal applicators typically incorporate internal shielding to reduce dose to the bladder and rectum. While dose distributions about a single colpostat have been extensively measured and calculated, these studies neglect dosimetric perturbations arising from the contralateral colpostat or the intrauterine tandem. Dosimetric effects of inhomogeneities in brachytherapy is essential for both dose-based implant optimization as well as for a comparison with alternate modalities, such as intensity modulated radiation therapy. We have used Monte Carlo calculations to model dose distributions about both a Fletcher-Suit-Delclos (FSD) low dose-rate system and the microSelectron high dose-rate remote afterloading system. We have evaluated errors, relative to a Monte Carlo simulation based upon a complete applicator system, in superposition calculations based upon both precalculated single shielded applicator dose distributions as well as single unshielded source dose distributions. Errors were largely dominated by the primary photon attenuation, and were largest behind the shields and tandem. For the FSD applicators, applicator superposition showed differences ranging from a mean of 2.6% at high doses (>Manchester Point A dose) to 4.3% at low doses (<Manchester Point A dose) compared to the full geometry simulation. Source-only superposition yielded errors higher than 10% throughout the dose range. For the HDR applicator system, applicator superposition-induced errors ranging from 3.6%-6.3% at high and low doses, respectively. Source superposition caused errors of 5%-11%. These results indicate that precalculated applicator-based dose distributions can provide an excellent approximation of a full geometry Monte Carlo dose calculation for gynecological implants.

Abutment region dosimetry for serial tomotherapy

PURPOSE A commercial intensity modulated radiation therapy system (Corvus, NOMOS Corp.) is presently used in our clinic to generate optimized dose distributions delivered using a proprietary dynamic multileaf collimator (DMLC) (MIMiC) composed of 20 opposed leaf pairs. On our accelerator (Clinac 600C/D, Varian Associates, Inc.) each MIMiC leaf projects to either 1.00 x 0.84 or 1.00 x 1.70 cm2 (depending on the treatment plan and termed 1 cm or 2 cm mode, respectively). The MIMiC is used to deliver serial (axial) tomotherapy treatment plans, in which the beam is delivered to a nearly cylindrical volume as the DMLC is rotated about the patient. For longer targets, the patient is moved (indexed) between treatments a distance corresponding to the projected leaf width. The treatment relies on precise indexing and a method was developed to measure the precision of indexing devices. A treatment planning study of the dosimetric effects of incorrect patient indexing and concluded that a dose heterogeneity of 10% mm(-1) resulted. Because the results may be sensitive to the dose model accuracy, we conducted a measurement-based investigation of the consequences of incorrect indexing using our accelerator. Although the indexing provides an accurate field abutment along the isocenter, due to beam divergence, hot and cold spots will be produced below and above isocenter, respectively, when less than 300 degree arcs were used. A preliminary study recently determined that for a 290 degree rotation in 1 cm mode, 15% cold and 7% hot spots were delivered to 7 cm above and below isocenter, respectively. This study completes the earlier work by investigating the dose heterogeneity as a function of position relative to the axis of rotation, arc length, and leaf width. The influence of random daily patient positioning errors is also investigated. METHODS AND MATERIALS Treatment plans were generated using 8.0 cm diameter cylindrical target volumes within a homogeneous rectilinear film phantom. The plans included both 1 and 2 cm mode, optimized for 300 degrees, 240 degrees, and 180 degrees gantry rotations. Coronal-oriented films were irradiated throughout the target volumes and scanned using a laser film digitizer. The central target irradiated in 1 cm mode was also used to investigate the effects of incorrect couch indexing. RESULTS The dose error as a function of couch index error was 25% mm(-1), significantly greater than previously reported. The clinically provided indexing system yielded 0.10 mm indexing precision. The intrinsic dose distributions indicated that more heterogeneous dose distributions resulted from the use of smaller gantry angle ranges and larger leaf projections. Using 300 degrees gantry angle and 1 cm mode yielded 7% hot and 15% cold spots 7 cm below and above isocenter, respectively. When a 180 degree gantry angle was used, the values changed to 22% hot and 27% cold spots for the same locations. The heterogeneities for the 2 cm mode were 70% greater than the corresponding 1 cm values. CONCLUSIONS While serial tomotherapy is used to deliver highly conformal dose distributions, significant dosimetric factors must be considered before treatment. The patient must be immobilized during treatment to avoid dose heterogeneities caused by incorrect indexing due to patient movement. Even under ideal conditions, beam divergence can cause significant abutment-region dose heterogeneities. The use of larger gantry angle ranges, smaller leaf widths, and appropriate locations of the gantry rotation axis can minimize these effects.

TOWARD AUTOMATED QUALITY ASSURANCE FOR INTENSITY- MODULATED RADIATION THERAPY

PURPOSE To investigate whether high-quality, relatively inexpensive, document and transparency scanners used as densitometers are sufficiently quantitative for routine quality assurance (QA). METHODS AND MATERIALS The scanner we investigated used a linear amplifier, digitizing gray-scale images to 12-bit resolution with a user-selected spatial resolution of 0.170 mm(2) pixels. To reduce Newtons rings artifacts, the standard glass platen was replaced by glass with an antireflective coating. Conversion of reading to transmission was conducted by permanently placing a calibrated photographic step tablet on the scanner platen. After conversion to light transmission, a zero-phase two-dimensional Wiener filter was used to reduce pixel-to-pixel signal variation. Light-scatter artifacts were removed by deconvolution of a measured light-spread kernel. The light-spread kernel artifacts were significant along the scanners detector axis, but were insignificant along the scanning axis. RESULTS Pixel-to-pixel noise was better than 2% for optical densities, ranging from 0.4 to 2.0 and 0 to 2.7 for the unfiltered and filtered images, respectively. The document scanning system response was compared against a confocal scanning laser densitometer. A series of IMRT dose distribution and dose calibration film sets were scanned using the two scanners, and the measured dose was compared. The maximum mean and standard deviation of the measured dose difference between the document scanner and confocal scanner was 1.48% and 1.06%, respectively. CONCLUSION While the document scanners are not as flexible as dedicated film densitometers, these results indicate that, using the intensity and scatter corrections, the system provides accurate and precise measurements up to an optical density of 2.0, sufficient for routine IMRT film QA. For some film types, this requires the reduction in monitor units to limit the dose delivered to the film. The user must be cautious that the delivered IMRT dose is scaled appropriately. This inexpensive and accurate system is being integrated into an automated QA program.

Noise in polymer gel measurements using MRI.

With the development of conformal radiotherapy, particularly intensity modulated radiation therapy (IMRT), there is a clear need for multidimensional dosimeters. A commercial polymerizing gel, BANG-2 gel (MGS Research, Inc., Guilford, CT), has recently been developed that shows potential as a multi-dimensional dosimeter. This study investigates and characterizes the noise and magnetic resonance (MR) artifacts from imaging BANG-2 gels. Seven cylindrical vials (4 cm diam, 20 cm length) were irradiated end on in a water bath and read using MRI (B0=1.5 T, TE=20 ms/100 ms, TR=3000 ms). The gel calibration compared the measured depth-dose distributions in water against the change in solvent-proton R2 relaxivity of the gel. A larger vial (13 cm diam, 14 cm length) was also irradiated to test the calibration accuracy in a vial of sufficient volume for dose distribution measurements. The calibration curve proved accurate to within 1.3% in determining the depth dose measured by the larger vial. An investigation of the voxel-to-voxel (IXIX 3 mm3) noise and sensitivity response curve showed that the voxel-to-voxel variation dominated the dose measurement uncertainty. The voxel-to-voxel standard deviation ranged from 0.2 Gy for the unirradiated gel to 0.7 Gy at 20 Gy. Slice-to-slice R2 magnitude deviations were also observed corresponding to 0.2 Gy. These variations limited the overall accuracy of the gel dose measurements and warrant an investigation of more accurate MR readout sequences.

An Iterative Algorithm for Solving Hamilton--Jacobi Type Equations

Solutions of the optimal control and