Parag J. Parikh

A method for the reconstruction of four-dimensional synchronized CT scans acquired during free breathing

Breathing motion is a significant source of error in radiotherapy treatment planning for the thorax and upper abdomen. Accounting for breathing motion has a profound effect on the size of conformal radiation portals employed in these sites. Breathing motion also causes artifacts and distortions in treatment planning computed tomography (CT) scans acquired during free breathing and also causes a breakdown of the assumption of the superposition of radiation portals in intensity-modulated radiation therapy, possibly leading to significant dose delivery errors. Proposed voluntary and involuntary breath-hold techniques have the potential for reducing or eliminating the effects of breathing motion, however, they are limited in practice, by the fact that many lung cancer patients cannot tolerate holding their breath. We present an alternative solution to accounting for breathing motion in radiotherapy treatment planning, where multislice CT scans are collected simultaneously with digital spirometry over many free breathing cycles to create a four-dimensional (4-D) image set, where tidal lung volume is the additional dimension. An analysis of this 4-D data leads to methods for digital-spirometry, based elimination or accounting of breathing motion artifacts in radiotherapy treatment planning for free breathing patients. The 4-D image set is generated by sorting free-breathing multislice CT scans according to user-defined tidal-volume bins. A multislice CT scanner is operated in the ciné mode, acquiring 15 scans per couch position, while the patient undergoes simultaneous digital-spirometry measurements. The spirometry is used to retrospectively sort the CT scans by their correlated tidal lung volume within the patients normal breathing cycle. This method has been prototyped using data from three lung cancer patients. The actual tidal lung volumes agreed with the specified bin volumes within standard deviations ranging between 22 and 33 cm3. An analysis of sagittal and coronal images demonstrated relatively small (<1 cm) motion artifacts along the diaphragm, even for tidal volumes where the rate of breathing motion is greatest. While still under development, this technology has the potential for revolutionizing the radiotherapy treatment planning for the thorax and upper abdomen.

RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the Reduction of Acute Morbidity in Carcinoma of the Anal Canal

PURPOSE A multi-institutional phase 2 trial assessed the utility of dose-painted intensity modulated radiation therapy (DP-IMRT) in reducing grade 2+ combined acute gastrointestinal and genitourinary adverse events (AEs) of 5-fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer by at least 15% compared with the conventional radiation/5FU/MMC arm from RTOG 9811. METHODS AND MATERIALS T2-4N0-3M0 anal cancer patients received 5FU and MMC on days 1 and 29 of DP-IMRT, prescribed per stage: T2N0, 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs) in 28 fractions; T3-4N0-3, 45 Gy elective nodal, 50.4 Gy ≤ 3 cm or 54 Gy >3 cm metastatic nodal and 54 Gy anal tumor PTVs in 30 fractions. The primary endpoint is described above. Planned secondary endpoints assessed all AEs and the investigators ability to perform DP-IMRT. RESULTS Of 63 accrued patients, 52 were evaluable. Tumor stage included 54% II, 25% IIIA, and 21% IIIB. In primary endpoint analysis, 77% experienced grade 2+ gastrointestinal/genitourinary acute AEs (9811 77%). There was, however, a significant reduction in acute grade 2+ hematologic, 73% (9811 85%, P=.032), grade 3+ gastrointestinal, 21% (9811 36%, P=.0082), and grade 3+ dermatologic AEs 23% (9811 49%, P<.0001) with DP-IMRT. On initial pretreatment review, 81% required DP-IMRT replanning, and final review revealed only 3 cases with normal tissue major deviations. CONCLUSIONS Although the primary endpoint was not met, DP-IMRT was associated with significant sparing of acute grade 2+ hematologic and grade 3+ dermatologic and gastrointestinal toxicity. Although DP-IMRT proved feasible, the high pretreatment planning revision rate emphasizes the importance of real-time radiation quality assurance for IMRT trials.

A comparison between amplitude sorting and phase-angle sorting using external respiratory measurement for 4D CT

Respiratory motion can cause significant dose delivery errors in conformal radiation therapy for thoracic and upper abdominal tumors. Four-dimensional computed tomography (4D CT) has been proposed to provide the image data necessary to model tumor motion and consequently reduce these errors. The purpose of this work was to compare 4D CT reconstruction methods using amplitude sorting and phase angle sorting. A 16-slice CT scanner was operated in ciné mode to acquire 25 scans consecutively at each couch position through the thorax. The patient underwent synchronized external respiratory measurements. The scans were sorted into 12 phases based, respectively, on the amplitude and direction (inhalation or exhalation) or on the phase angle (0-360 degrees) of the external respiratory signal. With the assumption that lung motion is largely proportional to the measured respiratory amplitude, the variation in amplitude corresponds to the variation in motion for each phase. A smaller variation in amplitude would associate with an improved reconstructed image. Air content, defined as the amount of air within the lungs, bronchi, and trachea in a 16-slice CT segment and used by our group as a surrogate for internal motion, was correlated to the respiratory amplitude and phase angle throughout the lungs. For the 35 patients who underwent quiet breathing, images (similar to those used for treatment planning) and animations (used to display respiratory motion) generated using amplitude sorting displayed fewer reconstruction artifacts than those generated using phase angle sorting. The variations in respiratory amplitude were significantly smaller (P < 0.001) with amplitude sorting than those with phase angle sorting. The subdivision of the breathing cycle into more (finer) phases improved the consistency in respiratory amplitude for amplitude sorting, but not for phase angle sorting. For 33 of the 35 patients, the air content showed significantly improved (P < 0.001) correlation with the respiratory amplitude than with the phase angle, suggesting a stronger relationship between internal motion and amplitude. Overall, amplitude sorting performed better than phase angle sorting for 33 of the 35 patients and equally well for two patients who were immobilized with a stereotactic body frame and an abdominal compression plate.

Quantitation of the reconstruction quality of a four-dimensional computed tomography process for lung cancer patients

We have developed a four-dimensional computed tomography (4D CT) technique for mapping breathing motion in radiotherapy treatment planning. A multislice CT scanner (1.5 mm slices) operated in ciné mode was used to acquire 12 contiguous slices in each couch position for 15 consecutive scans (0.5 s rotation, 0.25 s between scans) while the patient underwent simultaneous quantitative spirometry measurements to provide a sorting metric. The spirometry-sorted scans were used to reconstruct a 4D data set. A critical factor for 4D CT is quantifying the reconstructed data set quality which we measure by correlating the metric used relative to internal-object motion. For this study, the internal air content within the lung was used as a surrogate for internal motion measurements. Thresholding and image morphological operations were applied to delineate the air-containing tissues (lungs, trachea) from each CT slice. The Hounsfield values were converted to the internal air content (V). The relationship between the air content and spirometer-measured tidal volume (v) was found to be quite linear throughout the lungs and was used to estimate the overall accuracy and precision of tidal volume-sorted 4D CT. Inspection of the CT-scan air content as a function of tidal volume showed excellent correlations (typically r>0.99) throughout the lung volume. Because of the discovered linear relationship, the ratio of internal air content to tidal volume was indicative of the fraction of air change in each couch position. Theoretically, due to air density differences within the lung and in room, the sum of these ratios would equal 1.11. For 12 patients, the mean value was 1.08 +/- 0.06, indicating the high quality of spirometry-based image sorting. The residual of a first-order fit between v and V was used to estimate the process precision. For all patients, the precision was better than 8%, with a mean value of 5.1% +/- 1.9%. This quantitative analysis highlights the value of using spirometry as the metric in sorting CT scans. The 4D reconstruction provides the CT data required to measure the three-dimensional trajectory of tumor and lung tissue during free breathing.

MicroRT - Small animal conformal irradiator

A novel small animal conformal radiation therapy system has been designed and prototyped: MicroRT. The microRT system integrates multimodality imaging, radiation treatment planning, and conformal radiation therapy that utilizes a clinical 192Ir isotope high dose rate source as the radiation source (teletherapy). A multiparameter dose calculation algorithm based on Monte Carlo dose distribution simulations is used to efficiently and accurately calculate doses for treatment planning purposes. A series of precisely machined tungsten collimators mounted onto a cylindrical collimator assembly is used to provide the radiation beam portals. The current design allows a source-to-target distance range of 1-8 cm at four beam angles: 0 degrees (beam oriented down), 90 degrees, 180 degrees, and 270 degrees. The animal is anesthetized and placed in an immobilization device with built-in fiducial markers and scanned using a computed tomography, magnetic resonance, or positron emission tomography scanner prior to irradiation. Treatment plans using up to four beam orientations are created utilizing a custom treatment planning system-microRTP. A three-axis computer-controlled stage that supports and accurately positions the animals is programmed to place the animal relative to the radiation beams according to the microRTP plan. The microRT system positioning accuracy was found to be submillimeter. The radiation source is guided through one of four catheter channels and placed in line with the tungsten collimators to deliver the conformal radiation treatment. The microRT hardware specifications, the accuracy of the treatment planning and positioning systems, and some typical procedures for radiobiological experiments that can be performed with the microRT device are presented.

Toward submillimeter accuracy in the management of intrafraction motion: the integration of real-time internal position monitoring and multileaf collimator target tracking.

PURPOSE We report on an integrated system for real-time adaptive radiation delivery to moving tumors. The system combines two promising technologies-three-dimensional internal position monitoring using implanted electromagnetically excitable transponders and corresponding real-time beam adaptation using a dynamic multileaf collimator (DMLC). METHODS AND MATERIALS In a multi-institutional academic and industrial collaboration, a research version of the Calypso position monitoring system was integrated with a DMLC-based four-dimensional intensity-modulated radiotherapy delivery system using a Varian 120-leaf multileaf collimator (MLC). Two important determinants of system performance-latency (i.e., elapsed time between target motion and MLC response) and geometric accuracy-were investigated. Latency was quantified by acquiring continuous megavoltage X-ray images of a moving phantom (with embedded transponders) that was tracked in real time by a circular MLC field. The latency value was input into a motion prediction algorithm within the DMLC tracking system. Geometric accuracy was calculated as the root-mean-square positional error between the target and the centroid of the MLC aperture for patient-derived three-dimensional motion trajectories comprising two lung tumor traces and one prostate trace. RESULTS System latency was determined to be approximately 220 milliseconds. Tracking accuracy was observed to be sub-2 mm for the respiratory motion traces and sub-1 mm for prostate motion. CONCLUSION We have developed and characterized a research version of a novel four-dimensional delivery system that integrates nonionizing radiation-based internal position monitoring and accurate real-time DMLC-based beam adaptation. This system represents a significant step toward achieving the eventual goal of geometrically ideal dose delivery to moving tumors.

Dose-response for stereotactic body radiotherapy in early-stage non-small-cell lung cancer

PURPOSE To compare the efficacy of three lung stereotactic body radiotherapy (SBRT) regimens in a large institutional cohort. METHODS Between 2004 and 2009, 130 patients underwent definitive lung cancer SBRT to a single lesion at the Mallinckrodt Institute of Radiology. We delivered 18 Gy × 3 fractions for peripheral tumors (n = 111) and either 9 Gy × 5 fractions (n = 8) or 10 Gy × 5 fractions (n = 11) for tumors that were central or near critical structures. Univariate and multivariate analysis of prognostic factors was performed using the Cox proportional hazard model. RESULTS Median follow-up was 11, 16, and 13 months for the 9 Gy × 5, 10 Gy × 5, and 18 Gy × 3 groups, respectively. Local control statistics for Years 1 and 2 were, respectively, 75% and 50% for 9 Gy × 5, 100% and 100% for 10 Gy × 5, and 99% and 91% for 18 Gy × 3. Median overall survival was 14 months, not reached, and 34 months for the 9 Gy × 5, 10 Gy × 5, and 18 Gy × 3 treatments, respectively. No difference in local control or overall survival was found between the 10 Gy × 5 and 18 Gy × 3 groups on log-rank test, but both groups had improved local control and overall survival compared with 9 Gy × 5. Treatment with 9 Gy × 5 was the only independent prognostic factor for reduced local control on multivariate analysis, and increasing age, increasing tumor volume, and poor performance status predicted independently for reduced overall survival. CONCLUSION Treatment regimens of 10 Gy × 5 and 18 Gy × 3 seem to be efficacious for lung cancer SBRT and provide superior local control and overall survival compared with 9 Gy × 5.

Patterns of failure after stereotactic body radiation therapy or lobar resection for clinical stage I non-small-cell lung cancer.

Introduction: The purpose of this study was to compare patterns of failure between lobar resection (lobectomy or pneumonectomy) and stereotactic body radiation therapy (SBRT) for patients with clinical stage I non–small-cell lung cancer (NSCLC). Methods: From January 2004 to January 2008, 338 patients underwent definitive treatment for pathologically confirmed clinical stage I NSCLC with lobar resection (n = 260) or SBRT (n = 78). Most surgical patients underwent lobectomy (n = 237). SBRT patients received a biologically effective dose of at least 100 Gy10. Lobar resection patients were younger, healthier, and had superior pulmonary function, whereas most of the patients in the SBRT group had T1 tumors. Final pathology upstaged 32.7% of surgery patients, and 20.0% received adjuvant chemotherapy. No SBRT patients received adjuvant chemotherapy. Results: In an unmatched comparison, 4-year lobar local control (98.7% versus 93.6%, p = 0.015) was greater for lobar resection versus SBRT, respectively, though primary tumor (98.7% versus 95.3%, p = 0.088), regional (82.9% versus 78.1%, p = 0.912), and distant control (76.1% versus 54.0%, p = 0.152) were similar. Overall survival (OS, 63.5% versus 29.6%, p < 0.0001) was greater for lobar resection, though cause-specific survival (CSS, 81.3% versus 75.3%, p = 0.923) was similar. In a T-stage matched comparison of 152 patients, there was no significant difference in patterns of failure or CSS, whereas OS favored surgery. Conclusion: Lobectomy/pneumonectomy or SBRT results in comparable patterns of failure for clinical stage I NSCLC. In this retrospective comparison, OS was superior for surgery, though CSS was similar. Randomized trials are necessary to control for fundamental differences in comorbidity, which impact interpretation of both tumor control and survival.

Prediction of Intrafraction Prostate Motion: Accuracy of Pre- and Post-Treatment Imaging and Intermittent Imaging

PURPOSE To evaluate whether pre- and post-treatment imaging (immediately before and after a radiation therapy treatment fraction) and intermittent imaging (at intervals during a treatment fraction) are accurate predictors of prostate motion during the delivery of radiation. METHODS AND MATERIALS The Calypso 4D Localization System was used to continuously track the prostate during radiation delivery in 35 prostate cancer patients, for a total of 1,157 fractions (28-45 per patient). Predictions of prostate motion away from isocenter were modeled for a pre- and post-treatment imaging schedule and for multiple intermittent intrafraction imaging schedules and compared with the actual continuous tracking data. The endpoint was drift of the prostate beyond a certain radial displacement for a duration of more than 30 s, 1 min, and 2 min. Results were used to evaluate the sensitivity and specificity of these models as an evaluation of intrafraction prostate motion. RESULTS The sensitivity of pre- and post-treatment imaging in determining 30 s of intrafraction prostate motion greater than 3, 5, or 7 mm for all fractions was low, with values of 53%, 49%, and 39%, respectively. The specificity of pre- and post-treatment imaging was high for all displacements. The sensitivity of intermittent imaging improved with increasing sampling rate. CONCLUSIONS These results suggest that pre- and post-treatment imaging is not a sensitive method of assessing intrafraction prostate motion, and that intermittent imaging is sufficiently sensitive only at a high sampling rate. These findings support the value of continuous, real-time tracking in prostate cancer radiation therapy.

Comparison of spirometry and abdominal height as four-dimensional computed tomography metrics in lung

An important consideration in four-dimensional CT scanning is the selection of a breathing metric for sorting the CT data and modeling internal motion. This study compared two noninvasive breathing metrics, spirometry and abdominal height, against internal air content, used as a surrogate for internal motion. Both metrics were shown to be accurate, but the spirometry showed a stronger and more reproducible relationship than the abdominal height in the lung. The abdominal height was known to be affected by sensor placement and patient positioning while the spirometer exhibited signal drift. By combining these two, a normalization of the drift-free metric to tidal volume may be generated and the overall metric precision may be improved.