Joseph H. Killoran

A numerical simulation of organ motion and daily setup uncertainties: Implications for radiation therapy

PURPOSE In radiotherapy planning, the clinical target volume (CTV) is typically enlarged to create a planning target volume (PTV) that accounts for uncertainties due to internal organ and patient motion as well as setup error. Margin size clearly determines the volume of normal tissue irradiated, yet in practice it is often given a set value in accordance with a clinical precedent from which variations are rare. The (CTV/PTV) formalism does not account for critical structure dose. We present a numerical simulation to assess (CTV) coverage and critical organ dose as a function of treatment margins in the presence of organ motion and physical setup errors. An application of the model to the treatment of prostate cancer is presented, but the method is applicable to any site where normal tissue tolerance is a dose-limiting factor. METHODS AND MATERIALS A Monte Carlo approach was used to simulate the cumulative effect of variation in overall tumor position, for individual treatment fractions, relative to a fixed distribution of dose. Distributions of potential dose-volume histograms (DVHs), for both tumor and normal tissues, are determined that fully quantify the stochastic nature of radiotherapy delivery. We introduce the concept of Probability of Prescription Dose (PoPD) isosurfaces as a tool for treatment plan optimization. Outcomes resulting from current treatment planning methods are compared with proposed techniques for treatment optimization. The standard planning technique of relatively large uniform margins applied to the CTV, in the beams eye view (BEV), was compared with three other treatment strategies: (a) reduced uniform margins, (b) nonuniform margins adjusted to maximize normal tissue sparing, and (c) a reduced margin plan in which nonuniform fluence profiles were introduced to compensate for potential areas of reduced dose. RESULTS Results based on 100 simulated full course treatments indicate that a 10 mm CTV to PTV margin, combined with an additional 5 mm dosimetric margin, provides adequate CTV coverage in the presence of known treatment uncertainties. Nonuniform margins can be employed to reduce dose delivered to normal tissues while preserving CTV coverage. Nonuniform fluence profiles can also be used to further reduce dose delivered to normal tissues, though this strategy does result in higher dose levels delivered to a small volume of the CTV and normal tissues. CONCLUSIONS Monte Carlo-based treatment simulation is an effective means of assessing the impact of organ motion and daily setup error on dose delivery via external beam radiation therapy. Probability of Prescription Dose (PoPD) isosurfaces are a useful tool for the determination of nonuniform beam margins that reduce dose delivered to critical organs while preserving CTV dose coverage. Nonuniform fluence profiles can further alter critical organ dose with potential therapeutic benefits. Clinical consequences of this latter approach can only be assessed via clinical trials.

Evaluation of the combined effects of target size, respiratory motion and background activity on 3D and 4D PET/CT images

Gated (4D) PET/CT has the potential to greatly improve the accuracy of radiotherapy at treatment sites where internal organ motion is significant. However, the best methodology for applying 4D-PET/CT to target definition is not currently well established. With the goal of better understanding how to best apply 4D information to radiotherapy, initial studies were performed to investigate the effect of target size, respiratory motion and target-to-background activity concentration ratio (TBR) on 3D (ungated) and 4D PET images. Using a PET/CT scanner with 4D or gating capability, a full 3D-PET scan corrected with a 3D attenuation map from 3D-CT scan and a respiratory gated (4D) PET scan corrected with corresponding attenuation maps from 4D-CT were performed by imaging spherical targets (0.5-26.5 mL) filled with (18)F-FDG in a dynamic thorax phantom and NEMA IEC body phantom at different TBRs (infinite, 8 and 4). To simulate respiratory motion, the phantoms were driven sinusoidally in the superior-inferior direction with amplitudes of 0, 1 and 2 cm and a period of 4.5 s. Recovery coefficients were determined on PET images. In addition, gating methods using different numbers of gating bins (1-20 bins) were evaluated with image noise and temporal resolution. For evaluation, volume recovery coefficient, signal-to-noise ratio and contrast-to-noise ratio were calculated as a function of the number of gating bins. Moreover, the optimum thresholds which give accurate moving target volumes were obtained for 3D and 4D images. The partial volume effect and signal loss in the 3D-PET images due to the limited PET resolution and the respiratory motion, respectively were measured. The results show that signal loss depends on both the amplitude and pattern of respiratory motion. However, the 4D-PET successfully recovers most of the loss induced by the respiratory motion. The 5-bin gating method gives the best temporal resolution with acceptable image noise. The results based on the 4D scan protocols can be used to improve the accuracy of determining the gross tumor volume for tumors in the lung and abdomen.

Clinical Utility of 4D FDG-PET/CT Scans in Radiation Treatment Planning

PURPOSE The potential role of four-dimensional (4D) positron emission tomography (PET)/computed tomography (CT) in radiation treatment planning, relative to standard three-dimensional (3D) PET/CT, was examined. METHODS AND MATERIALS Ten patients with non-small-cell lung cancer had sequential 3D and 4D [(18)F]fluorodeoxyglucose PET/CT scans in the treatment position prior to radiation therapy. The gross tumor volume and involved lymph nodes were contoured on the PET scan by use of three different techniques: manual contouring by an experienced radiation oncologist using a predetermined protocol; a technique with a constant threshold of standardized uptake value (SUV) greater than 2.5; and an automatic segmentation technique. For each technique, the tumor volume was defined on the 3D scan (VOL3D) and on the 4D scan (VOL4D) by combining the volume defined on each of the five breathing phases individually. The range of tumor motion and the location of each lesion were also recorded, and their influence on the differences observed between VOL3D and VOL4D was investigated. RESULTS We identified and analyzed 22 distinct lesions, including 9 primary tumors and 13 mediastinal lymph nodes. Mean VOL4D was larger than mean VOL3D with all three techniques, and the difference was statistically significant (p < 0.01). The range of tumor motion and the location of the tumor affected the magnitude of the difference. For one case, all three tumor definition techniques identified volume of moderate uptake of approximately 1 mL in the hilar region on the 4D scan (SUV maximum, 3.3) but not on the 3D scan (SUV maximum, 2.3). CONCLUSIONS In comparison to 3D PET, 4D PET may better define the full physiologic extent of moving tumors and improve radiation treatment planning for lung tumors. In addition, reduction of blurring from free-breathing images may reveal additional information regarding regional disease.

Beam shaping for conformal fractionated stereotactic radiotherapy : A modeling study

PURPOSE The patient population treated with fractionated stereotactic radiotherapy (SRT) is significantly different than that treated with stereotactic radiosurgery (SRS). Generally, lesions treated with SRT are larger, less spherical, and located within critical regions of the central nervous system; hence, they offer new challenges to the treatment planner. Here a simple, cost effective, beam shaping system has been evaluated relative to both circular collimators and an ideal dynamically conforming system for effectiveness in providing conformal therapy for these lesions. METHODS AND MATERIALS We have modeled a simple system for conformal arc therapy using four independent jaws. The jaw positions and collimator angle are changed between arcs but held fixed for the duration of each arc. Eleven previously treated SRT cases have been replanned using this system. The rectangular jaw plans were then compared to the original treatment plans which used circular collimators. The plans were evaluated with respect to tissue sparing at 100%, 80%, 50%, and 20% of the prescription dose. A plan was also done for each tumor in which the beam aperture was continuously conformed to the beams eye view projection of the tumor. This was used as an ideal standard for conformal therapy in the absence of fluence modulation. RESULTS For tumors with a maximum extent of over 3.5 cm the rectangular jaw plans reduced the mean volume of healthy tissue involved at the prescription dose by 57% relative to the circular collimator plans. The ideal conformal plans offered no significant further improvement at the prescription dose. The relative advantage of the rectangular jaw plans decreased at lower isodoses so that at 20% of the prescription dose tissue involvement for the rectangular jaw plans was equivalent to that for the circular collimator plans. At these isodoses the ideal conformal plans gave substantially better tissue sparing. CONCLUSION A simple and economical field shaping device has been shown to provide all of the beam shaping advantage of a hypothetical ideal dynamically conforming system at the prescription level. This system may be immediately implemented in the clinic. It offers a substantial advantage over the currently used circular collimators in the high dose region with equivalent performance in the low dose region.

Impact of Manual and Automated Interpretation of Fused PET/CT Data on Esophageal Target Definitions in Radiation Planning

PURPOSE We compare CT-only based esophageal tumor definition with two PET/CT based methods: (1) manual contouring and (2) a semiautomated method based on specific thresholds. METHODS AND MATERIALS Patients with esophageal cancer treated at Brigham and Womens Hospital from 2003 to 2006 were identified. CT-based tumor volumes were compared with manual PET/CT-based volumes and semiautomated PET-based tumor volumes. Differences were scored as (1) minor if the superior or inferior extent of the primary tumor (or both) differed by 1-2 cm and (2) major if the difference was > 2 cm or if different noncontiguous nodal regions were identified as being grossly involved. RESULTS Comparing CT-based gross tumor volumes (GTVs) to manually defined PET/CT-based GTVs, use of PET changed volumes for 21 of 25 (84%) patients: 12 patients (48%) exhibited minor differences, whereas for 9 patients (36%), the differences were major. For 4 (16%) patients, the major difference was due to discrepancy in celiac or distant mediastinal lymph node involvement. Use of automated PET volumes changed the manual PET length in 14 patients (56%): 8 minor and 6 major. CONCLUSIONS The use of PET/CT in treatment planning for esophageal cancer can affect target definition. Two PET-based techniques can also produce significantly different tumor volumes in a large percentage of patients. Further investigations to clarify the optimal use of PET/CT data in treatment planning are warranted.

Low Incidence of Chest Wall Pain with a Risk-Adapted Lung Stereotactic Body Radiation Therapy Approach Using Three or Five Fractions Based on Chest Wall Dosimetry

Purpose To examine the frequency and potential of dose-volume predictors for chest wall (CW) toxicity (pain and/or rib fracture) for patients receiving lung stereotactic body radiotherapy (SBRT) using treatment planning methods to minimize CW dose and a risk-adapted fractionation scheme. Methods We reviewed data from 72 treatment plans, from 69 lung SBRT patients with at least one year of follow-up or CW toxicity, who were treated at our center between 2010 and 2013. Treatment plans were optimized to reduce CW dose and patients received a risk-adapted fractionation of 18 Gy×3 fractions (54 Gy total) if the CW V30 was less than 30 mL or 10–12 Gy×5 fractions (50–60 Gy total) otherwise. The association between CW toxicity and patient characteristics, treatment parameters and dose metrics, including biologically equivalent dose, were analyzed using logistic regression. Results With a median follow-up of 20 months, 6 (8.3%) patients developed CW pain including three (4.2%) grade 1, two (2.8%) grade 2 and one (1.4%) grade 3. Five (6.9%) patients developed rib fractures, one of which was symptomatic. No significant associations between CW toxicity and patient and dosimetric variables were identified on univariate nor multivariate analysis. Conclusions Optimization of treatment plans to reduce CW dose and a risk-adapted fractionation strategy of three or five fractions based on the CW V30 resulted in a low incidence of CW toxicity. Under these conditions, none of the patient characteristics or dose metrics we examined appeared to be predictive of CW pain.

Evaluating FDG uptake changes between pre and post therapy respiratory gated PET scans

PURPOSE Whole body (3D) and respiratory gated (4D) FDG-PET/CT scans performed pre-radiotherapy (pre-RT) and post-radiotherapy (post-RT) were analyzed to investigate the impact of 4D PET in evaluating 18F-fluorodeoxyglucose (FDG) uptake changes due to therapy, relative to traditional 3D PET. METHODS AND MATERIALS 3D and 4D sequential FDG-PET/CT scans were acquired pre-RT and approximately one month post-RT for patients with non-small cell lung cancer (NSCLC). The lesions of high uptake targeted with radiotherapy were identified on the pre-RT scan of each patient. Each lesion on the 3D and each of the five phases of the 4D scan were analyzed using a region of interest (ROI). For each patient the ROIs of the pre-RT scans were used to locate the areas of initial FDG uptake on the post-RT scans following rigid registration. Post-RT ROIs were drawn and the FDG uptake was compared with that of the pre-RT scans. RESULTS Sixteen distinct lesions from 12 patients were identified and analyzed. Standardized uptake value (SUV) maxima were significantly higher (p-value <0.005) for the lesions as measured on the 4D compared to 3D PET. Comparison of serial pre and post-RT scans showed a mean 62% decrease in SUV with the 3D PET scan (range 36-89%), and a 67% decrease with the 4D PET scan (range 30-89%). The mean absolute difference in SUV change on 3D versus 4D scans was 4.9%, with a range 0-15% (p-value = 0.07). CONCLUSIONS Signal recovery with 4D PET results in higher SUVs when compared to standard 3D PET. Consequently, differences in the evaluation of SUV changes between pre and post-RT plans were observed. Such difference can have a significant impact in PET-based response assessment.

Motion artifacts occurring at the lung/diaphragm interface using 4D CT attenuation correction of 4D PET scans

For PET/CT, fast CT acquisition time can lead to errors in attenuation correction, particularly at the lung/diaphragm interface. Gated 4D PET can reduce motion artifacts, though residual artifacts may persist depending on the CT dataset used for attenuation correction. We performed phantom studies to evaluate 4D PET images of targets near a density interface using three different methods for attenuation correction: a single 3D CT (3D CTAC), an averaged 4D CT (CINE CTAC), and a fully phase matched 4D CT (4D CTAC). A phantom was designed with two density regions corresponding to diaphragm and lung. An 8 mL sphere phantom loaded with 18F‐FDG was used to represent a lung tumor and background FDG included at an 8:1 ratio. Motion patterns of sin(x) and sin4(x) were used for dynamic studies. Image data was acquired using a GE Discovery DVCT‐PET/CT scanner. Attenuation correction methods were compared based on normalized recovery coefficient (NRC), as well as a novel quantity “fixed activity volume” (FAV) introduced in our report. Image metrics were compared to those determined from a 3D PET scan with no motion present (3D STATIC). Values of FAV and NRC showed significant variation over the motion cycle when corrected by 3D CTAC images. 4D CTAC‐ and CINE CTAC–corrected PET images reduced these motion artifacts. The amount of artifact reduction is greater when the target is surrounded by lower density material and when motion was based on sin4(x). 4D CTAC reduced artifacts more than CINE CTAC for most scenarios. For a target surrounded by water equivalent material, there was no advantage to 4D CTAC over CINE CTAC when using the sin(x) motion pattern. Attenuation correction using both 4D CTAC or CINE CTAC can reduce motion artifacts in regions that include a tissue interface such as the lung/diaphragm border. 4D CTAC is more effective than CINE CTAC at reducing artifacts in some, but not all, scenarios. PACS numbers: 87.57.qp, 87.57.cp

Inter fractional variability of breathing phase definition as determined by fiducial location

Reconstruction of four-dimensional (4D) imaging typically requires an externally measurable surrogate to represent the real-time relative phase of respiration. A common method is to use a reflective marker on the external surface of the patient which moves with respiration and can be tracked in real time. The location of the marker is often chosen to maximize the observable motion, though this location may not be at the region of interest. We evaluate the importance of infrared (IR) marker placement location on breathing phase definition for the purpose of respiratory gating and 4D computed tomography (CT) image reconstruction. Data were collected for ten patients enrolled on an approved IRB protocol. Real-time position data were collected during CT imaging and daily treatments for two external IR reflective markers: one placed near the xyphoid and another at the approximate location of the treatment isocenter. Motion traces from the markers were compared using cross-correlation coefficient and by estimating the relative respiratory phase, based on either marker, as would be used for 4D-CT reconstruction. Cross-correlation analysis revealed differences in the motion waveform, as well as phase differences, both of which were variable between patients as well as day to day for the same patient. Estimated relative phases from each marker were compared by the percentage amount of time the estimated phase for each marker was different, binned based on increments of 10% of a full cycle. For all collected data combined, the frequency with which breathing phase mismatch led to different bin allocation in steps of 10% was as follows: T0%-10% = 65.1%, T10%-20% = 25.3%, T20%-30% = 7.8%, T30%-40% = 1.5% and T40%-50% = 0.4%. Based on ten images per cycle, this indicates that 4D reconstructions would be influenced, depending on which marker was used, by at least 1 bin 34.9% of the time. This number was noticeably higher for some patients; the maximum was 71% of the time for one patient of ten. In conclusion, the respiratory amplitude and relative phase depend significantly on the location of the IR marker used to monitor respiration. For some patients the xyphoid and isocentric markers may be completely out of phase. More importantly, this relationship varies day to day, suggesting that a single marker may be inadequate for the purposes of respiratory gating.

An independent dose calculation algorithm for MLC-based stereotactic radiotherapy

We have developed an algorithm to calculate dose in a homogeneous phantom for radiotherapy fields defined by multi-leaf collimator (MLC) for both static and dynamic MLC delivery. The algorithm was developed to supplement the dose algorithms of the commercial treatment planning systems (TPS). The motivation for this work is to provide an independent dose calculation primarily for quality assurance (QA) and secondarily for the development of static MLC field based inverse planning. The dose calculation utilizes a pencil-beam kernel. However, an explicit analytical integration results in a closed form for rectangular-shaped beamlets, defined by single leaf pairs. This approach reduces spatial integration to summation, and leads to a simple method of determination of model parameters. The total dose for any static or dynamic MLC field is obtained by summing over all individual rectangles from each segment which offers faster speed to calculate two-dimensional dose distributions at any depth in the phantom. Standard beam data used in the commissioning of the TPS was used as input data for the algorithm. The calculated results were compared with the TPS and measurements for static and dynamic MLC. The agreement was very good (<2.5%) for all tested cases except for very small static MLC sizes of 0.6 cm x 0.6 cm (<6%) and some ion chamber measurements in a high gradient region (<4.4%). This finding enables us to use the algorithm for routine QA as well as for research developments.