Boris Mueller

Advances in 4D Medical Imaging and 4D Radiation Therapy

This paper reviews recent advances in 4D medical imaging (4DMI) and 4D radiation therapy (4DRT), which study, characterize, and minimize patient motion during the processes of imaging and radiotherapy. Patient motion is inevitably present in these processes, producing artifacts and uncertainties in target (lesion) identification, delineation, and localization. 4DMI includes time-resolved volumetric CT, MRI, PET, PET/CT, SPECT, and US imaging. To enhance the performance of these volumetric imaging techniques, parallel multi-detector array has been employed for acquiring image projections and the volumetric image reconstruction has been advanced from the 2D to the 3D tomography paradigm. The time information required for motion characterization in 4D imaging can be obtained either prospectively or retrospectively using respiratory gating or motion tracking techniques. The former acquires snapshot projections for reconstructing a motion-free image. The latter acquires image projections continuously with an associated timestamp indicating respiratory phases using external surrogates and sorts these projections into bins that represent different respiratory phases prior to reconstructing the cyclical series of 3D images. These methodologies generally work for all imaging modalities with variations in detailed implementation. In 4D CT imaging, both multi-slice CT (MSCT) and cone-beam CT (CBCT) are applicable in 4D imaging. In 4D MR imaging, parallel imaging with multi-coil-detectors has made 4D volumetric MRI possible. In 4D PET and SPECT, rigid and non-rigid motions can be corrected with aid of rigid and deformable registration, respectively, without suffering from low statistics due to signal binning. In 4D PET/CT and SPECT/CT, a single set of 4D images can be utilized for motion-free image creation, intrinsic registration, and attenuation correction. In 4D US, volumetric ultrasonography can be employed to monitor fetal heart beating with relatively high temporal resolution. 4DRT aims to track and compensate for target motion during radiation treatment, minimizing normal tissue injury, especially critical structures adjacent to the target, and/or maximizing radiation dose to the target. 4DRT requires 4DMI, 4D radiation treatment planning (4D RTP), and 4D radiation treatment delivery (4D RTD). Many concepts in 4DRT are borrowed, adapted and extended from existing image-guided radiation therapy (IGRT) and adaptive radiation therapy (ART). The advantage of 4DRT is its promise of sparing additional normal tissue by synchronizing the radiation beam with the moving target in real-time. 4DRT can be implemented differently depending upon how the time information is incorporated and utilized. In an ideal situation, the motion adaptive approach guided by 4D imaging should be applied to both RTP and RTD. However, until new automatic planning and motion feedback tools are developed for 4DRT, clinical implementation of ideal 4DRT will meet with limited success. However, simplified forms of 4DRT have been implemented with minor modifications of existing planning and delivery systems. The most common approach is the use of gating techniques in both imaging and treatment, so that the planned and treated target localizations are identical. In 4D planning, the use of a single planning CT image, which is representative of the statistical respiratory mean, seems preferable. In 4D delivery, on-site CBCT imaging or 3D US localization imaging for patient setup and internal fiducial markersfor target motion tracking can significantly reduce the uncertainty in treatment delivery, providing improved normal tissue sparing. Most of the work on 4DRT can be regarded as a proof-of-principle and 4DRT is still in its early stage of development.

Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III–IVB head and neck squamous cell carcinoma (HNSCC)

BACKGROUND There is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes. PATIENTS AND METHODS This was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored (30, 45, 60, and 80 mg/m2), given with standard weekly cetuximab (450 mg/m2 loading dose followed by 250 mg/m2 weekly) and concurrent IMRT (total dose, 70 Gy). RESULTS Twenty-five eligible patients (20 M, 5 F) enrolled, with median age 58 years (range, 46-84 years). Primary tumor sites were oropharynx, 19 (10 human papillomavirus [HPV] pos, 8 HPV neg, 1 not done); neck node with unknown primary, 2; larynx 2; and oral cavity and maxillary sinus, 1 each. Seven patients had received prior induction chemotherapy. Maximum tolerated dose (MTD) was exceeded at DL4 (nab-paclitaxel, 80 mg/m2) with three dose-limiting toxicities (DLTs) (grade 3 neuropathy, grade 3 dehydration, with grade 3 mucositis grade 3 anemia) among five assessable patients. There was only one DLT (grade 3 supraventricular tachycardia) among six patients at DL3 (nab-paclitaxel, 60 mg/m2), and this was deemed the MTD. Among 23 assessable patients, the most common ≥ g3 AEs were lymphopenia 100%, functional mucositis 65%, and pain in throat/oral cavity 52%. At a median follow-up of 33 months, 2-year failure-free survival (FFS) is 65% [95% confidence interval (CI) 42% to 81%] and 2-year overall survival (OS) is 91% (95% CI 69-97). CONCLUSION The recommended phase II dose for nab-paclitaxel is 60 mg/m2 weekly when given standard weekly cetuximab and concurrent IMRT. This regimen merits further study as a nonplatinum alternative to IMRT + cetuximab alone. CLINICALTRIALS. GOV ID NCT00736619.BACKGROUND There is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes. PATIENTS AND METHODS This was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored (30, 45, 60, and 80 mg/m(2)), given with standard weekly cetuximab (450 mg/m(2) loading dose followed by 250 mg/m(2) weekly) and concurrent IMRT (total dose, 70 Gy). RESULTS Twenty-five eligible patients (20 M, 5 F) enrolled, with median age 58 years (range, 46-84 years). Primary tumor sites were oropharynx, 19 (10 human papillomavirus [HPV] pos, 8 HPV neg, 1 not done); neck node with unknown primary, 2; larynx 2; and oral cavity and maxillary sinus, 1 each. Seven patients had received prior induction chemotherapy. Maximum tolerated dose (MTD) was exceeded at DL4 (nab-paclitaxel, 80 mg/m(2)) with three dose-limiting toxicities (DLTs) (grade 3 neuropathy, grade 3 dehydration, with grade 3 mucositis grade 3 anemia) among five assessable patients. There was only one DLT (grade 3 supraventricular tachycardia) among six patients at DL3 (nab-paclitaxel, 60 mg/m(2)), and this was deemed the MTD. Among 23 assessable patients, the most common ≥ g3 AEs were lymphopenia 100%, functional mucositis 65%, and pain in throat/oral cavity 52%. At a median follow-up of 33 months, 2-year failure-free survival (FFS) is 65% [95% confidence interval (CI) 42% to 81%] and 2-year overall survival (OS) is 91% (95% CI 69-97). CONCLUSION The recommended phase II dose for nab-paclitaxel is 60 mg/m(2) weekly when given standard weekly cetuximab and concurrent IMRT. This regimen merits further study as a nonplatinum alternative to IMRT + cetuximab alone. CLINICALTRIALSGOV ID NCT00736619.

Dosimetric Effects of Gantry Angular Acceleration and Deceleration in Volumetric Modulated Radiation Therapy

Preliminary studies have shown that Volumetric modulated radiation therapy (VMAT) is a promising and competitive radiation treatment modality and could replace conventional intensity modulated radiation therapy (IMRT) for certain disease sites. Contrast to direct aperture optimization (DAO) adopted in intensity modulated arc therapy (IMAT), where MLC apertures are pre-defined and are not included in optimization, VMAT optimizes both MLC apertures and monitor unit (MU) weights. In addition, VMAT uses a much higher gantry angle sampling frequency to better model the continuously moving source. Thus, a desirable dose distribution can be achieved through MLC aperture modulation, dose rate modulation, and gantry angular speed modulation. Unlike conventional rotational techniques, in which the gantry rotates at a uniform angular speed from one segment to the next during treatment, VMAT requires the gantry to accelerate and decelerate frequently to deliver a given angular dose rate (MU/degree). This could potentially become a source of dosimetric error and compromise the plan quality. In this study, we investigated the dosimetric effects of gantry angular acceleration and deceleration in VMAT. Here, we report our initial results of the study. As far as we know, this is the first study of this kind on VMAT and RapidArc in the field.

The development of a novel radiation treatment modality – volumetric modulated arc therapy

Recent theoretical studies and clinical investigations have indicated that volumetric modulated arc therapy (VMAT) can produce equal or better treatment plans than intensity modulated radiation therapy (IMRT), while achieving a significant reduction in treatment time. Built upon the concept of aperture-based multi-level beam source sampling optimization, VMAT has overcome many engineering constraints and become a clinically viable radiation treatment modality. At this point in time, however, there are only two commercial VMAT treatment planning systems (TPS) on the market, which severely limit the dissemination of this novel technology. To address this issue, we recently have successfully developed our own version of VMAT TPS. In this paper, we present our preliminary test results.

A Systematic Approach to Patient Specific QA For Volumetric Modulated Arc Therapy (VMAT)

We developed the first non-commercial treatment planning system for volumetric modulated radiation therapy (VMAT) in the United States. Because VMAT involves multiparameter modulations, it is imperative to develop a comprehensive, rigorous and yet, practical procedure for routine patient-specific quality assurance (QA). In this paper, we present our own approach as being currently implemented in our institution. Our patient-specific QA procedure involves multi-levels: pre-treatment QA, on-treatment QA, and posttreatment QA. The pre-treatment QA focuses on dosimetry verification. It is done with the commercial MapCHECK in MapPHAN mounted on an isocentric mounting fixture (IMF). This method is also referred to as the fixed-gantry technique, i.e., the beams always remain perpendicular to the detector plane. The on-treatment QA involves in-vivo optically stimulated luminescent dosimetry (OSLD). Prior to the treatment, two nanoDot TM OSLD dosimeters are placed on the patient abdomen under 1 cm bolus at the isocenter location. The irradiated dosimeters are then read by a nanoDotTM reader and the average reading of the two is calculated. The post-treatment QA involves the analysis of the DynaLog and DLog files. The DynaLog is a treatment log file that contains the planned and actual leaf positions at a given gantry angle. The DLog is a treatment log file that contains the planned segmented treatment table (STT) and the corresponding segment boundary samples, i.e., the actual delivered MU and gantry angle increment at each control point.

Feasibility of implementing stereotactic body radiation therapy using a non-commercial volumetric modulated arc therapy treatment planning system for early stage lung cancer

Nearly 25% of patients diagnosed with early-stage non-small cell lung carcinomas (NSCLC) are medically inoperable. For these patients, the radial stereotactic body radiation therapy (SBRT), planned and delivered with intensity modulated radiation therapy (IMRT) techniques, offers the only curative option. However, IMRT-SBRT has three significant deficiencies: an elevated beam-on time (MU); a reduced MU-to-cGy coefficient; and a prolonged delivery time. To address these issues, we have developed our in-house version of volumetric modulated arc therapy (VMAT). In this preliminary study, we compared VMAT-SBRT with IMRT-SBRT in terms of optimization, dosimetry, and delivery. Our goal was to investigate the feasibility of replacing the exiting IMRT-SBRT with VMAT-SBRT as a safe and viable alternative radiation modality for early-stage NSCLC.

A hybrid method for reliable registration of digitally reconstructed radiographs and kV x-ray images for image-guided radiation therapy for prostate cancer

Prostate cancer is the most common tumor site treated with intensity modulated radiation therapy (IMRT). However, due to patient and organ motions, treatment-induced physiological changes, and different daily filling in the bladder and rectum, the position of the prostate in relation to the fixed pelvic bone can change significantly. Without a reliable guiding technique, this could result in underdosing the target and overdosing the critical organs. Therefore, image-guided localization of the prostate must be performed prior to each treatment, which led to the development of a new radiation treatment modality, the image-guided radiation therapy (IGRT). One form of IGRT is to implant three gold seed markers into the prostate gland to serve as a fixed reference system. Daily patient setup verification is performed by using the gold seed markers-based image registration rather than the commonly used bony landmarks-based approach. In this paper, we present an efficient and automated method for registering digitally reconstructed radiographs (DRR) and kV X-ray images of the prostate with high accuracy using a hybrid method. Our technique relies on both internal fiducial markers (i.e. gold seed markers) implanted into the prostate and a robust, hybrid 2D registration method using a salient-region based image registration technique. The registration procedure consists of several novel steps. Validation experiments were performed to register DRR and kV X-ray images in anterior-posterior (AP) or lateral views and the results were reviewed by experienced radiation oncology physicists.

Phase impact factor: a novel parameter for determining optimal CT phase in 4D radiation therapy treatment planning for mobile lung cancer

Due to respiratory motion, lung tumor can move up to several centimeters. If respiratory motion is not carefully considered during the radiation treatment planning, the highly conformal dose distribution with steep gradients could miss the target. To address this issue, the common strategy is to add a population-derived safety margin to the gross tumor volume (GTV). However, during a free breathing CT simulation, the images could be acquired at any phase of a breathing cycle. With such a generalized uniform margin, the planning target volume (PTV) may either include more normal lung tissue than required or miss the GTV at certain phases of a breathing cycle. Recently, respiration correlated CT (4DCT) has been developed and implemented. With 4DCT, it is now possible to trace the tumor 3D trajectories during a breathing cycle and to define the tumor volume as the union of these 3D trajectories. The tumor volume defined in this way is called the internal target volume (ITV). In this study, we introduced a novel parameter, the phase impact factor (PIF), to determine the optimal CT phase for intensity modulated radiation therapy (IMRT) treatment planning for lung cancer. A minimum PIF yields a minimum probability for the GTV to move out of the ITV during the course of an IMRT treatment, providing a minimum probability of a geometric miss. Once the CT images with the optimal phase were determined, an IMRT plan with three to five co-planner beams was computed and optimized using the inverse treatment planning technique.

SU-F-T-562: Validation of EPID-Based Dosimetry for FSRS Commissioning

PURPOSE The prevailing approach to frameless SRS (fSRS) small field dosimetry is Gafchromic film. Though providing continuous information, its intrinsic uncertainties in fabrication, response, scan, and calibration often make film dosimetry subject to different interpretations. In this study, we explored the feasibility of using EPID portal dosimetry as a viable alternative to film for small field dosimetry. METHODS Plans prescribed a dose of 21 Gy were created on a flat solid water phantom with Eclipse V11 and iPlan for small static square fields (1.0 to 3.0 cm). In addition, two clinical test plans were computed by employing iPlan on a CIRS Kesler head phantom for target dimensions of 1.2cm and 2.0cm. Corresponding portal dosimetry plans were computed using the Eclipse TPS and delivered on a Varian TrueBeam machine. EBT-XD film dosimetry was performed as a reference. The isocenter doses were measured using EPID, OSLD, stereotactic diode, and CC01 ion chamber. RESULTS EPID doses at the center of the square field were higher than Eclipse TPS predicted portal doses, with the mean difference being 2.42±0.65%. Doses measured by EBT-XD film, OSLD, stereotactic diode, and CC01 ion chamber revealed smaller differences (except OSLDs), with mean differences being 0.36±3.11%, 4.12±4.13%, 1.7±2.76%, 1.45±2.37% for Eclipse and -1.36±0.85%, 2.38±4.2%, -0.03±0.50%, -0.27±0.78% for iPlan. The profiles measured by EPID and EBT-XD film resembled TPS (Eclipse and iPlan) predicted ones within 3.0%. For the two clinical test plans, the EPID mean doses at the center of field were 2.66±0.68% and 2.33±0.32% higher than TPS predicted doses. CONCLUSION We found that results obtained with EPID portal dosimetry were slightly higher (∼2%) than those obtained with EBT-XD film, diode, and CC01 ion chamber with the exception of OSLDs, but well within IROC tolerance (5.0%). Therefore, EPID has the potential to become a viable real-time alternative method to film dosimetry.

SU‐C‐108‐03: Investigation of MLC Leaf Tolerance and Dose Accuracy in VMAT Delivery

PURPOSE VMAT employs a multi-parameter modulation methodology. It tends to perform less reliably than the one-dimensional IMRT. Therefore, setting a suitable leaf positioning tolerance on the machine is crucial. In this study, we investigated the relationship between the leaf tolerance and the dose delivery accuracy for VMAT SBRT lung plans. The goal was to determine the optimal leaf tolerance for daily VMAT SBRT treatments. METHODS The study was performed on a VMAT-enabled Trilogy LINAC. To minimize the systematic bias in leaf and gantry speeds, all the VMAT SBRT plans had a prescription dose of 1800 cGy × 3. Prior to each plan delivery, the leaf positioning tolerance was reset to a new value in Machine Hardware Configuration in Treatment Administration. Upon completion of the plan delivery, the Dynalog Files and, more importantly, the Treatment Log File, i.e., the Dlog File, were saved and exported for post-processing. For our initial investigation, we tested leaf tolerance values of 1, 2, 3, 4, 5, and 6 mm, respectively. RESULTS We found that when the leaf tolerance was set to a tighter value, such as 1, 2, and 3 mm, a good delivery accuracy was preserved without any MLC interlock occurrences. However, when the leaf tolerance was increased to be greater than a threshold value, such as 3 mm in this case, the delivery accuracy deteriorated almost linearly beyond that point. We also found that except for the leaf tolerance = 1 mm, the gantry angle accuracy virtually remained unchanged as the leaf tolerance was increased, indicating a decoupling between the leaf tolerance and the gantry angle uncertainty. CONCLUSION We recommend that for VMAT SBRT lung plans with a prescription dose of 1800 cGy × 3, the optimal leaf tolerance should be set to 3 mm.