Liyong Lin

First Clinical Investigation of Cone Beam Computed Tomography and Deformable Registration for Adaptive Proton Therapy for Lung Cancer

PURPOSE An adaptive proton therapy workflow using cone beam computed tomography (CBCT) is proposed. It consists of an online evaluation of a fast range-corrected dose distribution based on a virtual CT (vCT) scan. This can be followed by more accurate offline dose recalculation on the vCT scan, which can trigger a rescan CT (rCT) for replanning. METHODS AND MATERIALS The workflow was tested retrospectively for 20 consecutive lung cancer patients. A diffeomorphic Morphon algorithm was used to generate the lung vCT by deforming the average planning CT onto the CBCT scan. An additional correction step was applied to account for anatomic modifications that cannot be modeled by deformation alone. A set of clinical indicators for replanning were generated according to the water equivalent thickness (WET) and dose statistics and compared with those obtained on the rCT scan. The fast dose approximation consisted of warping the initial planned dose onto the vCT scan according to the changes in WET. The potential under- and over-ranges were assessed as a variation in WET at the targets distal surface. RESULTS The range-corrected dose from the vCT scan reproduced clinical indicators similar to those of the rCT scan. The workflow performed well under different clinical scenarios, including atelectasis, lung reinflation, and different types of tumor response. Between the vCT and rCT scans, we found a difference in the measured 95% percentile of the over-range distribution of 3.4 ± 2.7 mm. The limitations of the technique consisted of inherent uncertainties in deformable registration and the drawbacks of CBCT imaging. The correction step was adequate when gross errors occurred but could not recover subtle anatomic or density changes in tumors with complex topology. CONCLUSIONS A proton therapy workflow based on CBCT provided clinical indicators similar to those using rCT for patients with lung cancer with considerable anatomic changes.

Particle Therapy for Non-Small Cell Lung Tumors: Where Do We Stand? A Systematic Review of the Literature

This review article provides a systematic overview of the currently available evidence on the clinical effectiveness of particle therapy for the treatment of non-small cell lung cancer and summarizes findings of in silico comparative planning studies. Furthermore, technical issues and dosimetric uncertainties with respect to thoracic particle therapy are discussed.

Effect of solar particle event radiation and hindlimb suspension on gastrointestinal tract bacterial translocation and immune activation.

The environmental conditions that could lead to an increased risk for the development of an infection during prolonged space flight include: microgravity, stress, radiation, disturbance of circadian rhythms, and altered nutritional intake. A large body of literature exists on the impairment of the immune system by space flight. With the advent of missions outside the Earths magnetic field, the increased risk of adverse effects due to exposure to radiation from a solar particle event (SPE) needs to be considered. Using models of reduced gravity and SPE radiation, we identify that either 2 Gy of radiation or hindlimb suspension alone leads to activation of the innate immune system and the two together are synergistic. The mechanism for the transient systemic immune activation is a reduced ability of the GI tract to contain bacterial products. The identification of mechanisms responsible for immune dysfunction during extended space missions will allow the development of specific countermeasures.

Experimental characterization of two-dimensional pencil beam scanning proton spot profiles

Dose calculations of pencil beam scanning treatment plans rely on the accuracy of proton spot profiles; not only the primary component but also the broad tail components. Four films are placed at several locations in air and multiple depths in Solidwater® for six selected energies. The films used for the primary components are exposed to 50-200 MU to avoid saturation; the films used for the tail components are exposed to 800, 8000 and 80,000 MU. By applying a pair/magnification method and merging these data, dose kernels down to 10(-4) of the central spot dose can be generated. From these kernels one can calculate the dose-per-MU for different field sizes and shapes. Measurements agree within 1% of dose-kernel-based calculations for output versus field size comparisons. Asymmetric, comet-shaped profile tails have a bigger impact at superficial depths and low energies: the output difference between two orientations at the surface of a rectangular field of 40 mm×200 mm is about 2% at the isocentre at 100 MeV. Integration of these dose kernels from 0 to 40 mm radius shows that the charge deficit in the Bragg peak chamber varies <2% from entrance to the end of range for energies <180 MeV, but exceeds 5% at 225 MeV.

Leukocyte Activity Is Altered in a Ground Based Murine Model of Microgravity and Proton Radiation Exposure

Immune system adaptation during spaceflight is a concern in space medicine. Decreased circulating leukocytes observed during and after space flight infer suppressed immune responses and susceptibility to infection. The microgravity aspect of the space environment has been simulated on Earth to study adverse biological effects in astronauts. In this report, the hindlimb unloading (HU) model was employed to investigate the combined effects of solar particle event-like proton radiation and simulated microgravity on immune cell parameters including lymphocyte subtype populations and activity. Lymphocytes are a type of white blood cell critical for adaptive immune responses and T lymphocytes are regulators of cell-mediated immunity, controlling the entire immune response. Mice were suspended prior to and after proton radiation exposure (2 Gy dose) and total leukocyte numbers and splenic lymphocyte functionality were evaluated on days 4 or 21 after combined HU and radiation exposure. Total white blood cell (WBC), lymphocyte, neutrophil, and monocyte counts are reduced by approximately 65%, 70%, 55%, and 70%, respectively, compared to the non-treated control group at 4 days after combined exposure. Splenic lymphocyte subpopulations are altered at both time points investigated. At 21 days post-exposure to combined HU and proton radiation, T cell activation and proliferation were assessed in isolated lymphocytes. Cell surface expression of the Early Activation Marker, CD69, is decreased by 30% in the combined treatment group, compared to the non-treated control group and cell proliferation was suppressed by approximately 50%, compared to the non-treated control group. These findings reveal that the combined stressors (HU and proton radiation exposure) result in decreased leukocyte numbers and function, which could contribute to immune system dysfunction in crew members. This investigation is one of the first to report on combined proton radiation and simulated microgravity effects on hematopoietic, specifically immune cells.

Experimental characterization of two-dimensional spot profiles for two proton pencil beam scanning nozzles.

Dose calculation for pencil beam scanning proton therapy requires accurate measurement of the broad tails of the proton spot profiles for every nozzle in clinical use. By applying a pair/magnification method and merging film data, 200 mm × 240 mm dose kernels extending to 10(-4) of the central spot dose are generated for six selected energies of the IBA dedicated and universal nozzles (DN and UN). One-dimensional, circular profiles up to 100 mm in radius are generated from the asymmetric profiles to facilitate spot profile comparison. For the highest energy, 225 MeV, the output of both the DN and the UN for field sizes from 40 to 200 mm increases in parallel, slowest at the surface (∼1%) and fastest at a depth of 150 mm (∼9%). In contrast, at the lowest energy, 100 MeV, the output of the DN across the same range of field sizes increases 3-4% versus 6-7% for the UN throughout all the depths. The charge deficits in the measured depth-dose of Bragg peaks are similar between the UN and the DN. At 100 MeV, the field size factor difference at the surface between two orientations of a rectangular 40 mm × 200 mm field is 1.4% at isocentre for the DN versus 2% for the UN. Though the one-dimensional distributions are similar for the primary and tail components at different positions, the primary components of the DN spots are more elliptical 270 mm upstream than at isocentre.

The use of directional interstitial sources to improve dosimetry in breast brachytherapy

The purposes of this study were to investigate the feasibility of improving dosimetry with temporary low-dose-rate (LDR) multicatheter breast implants using directional 125I (iodine) interstitial sources and to provide a comparison of a patient treatment plan to that achieved by conventional high-dose-rate (HDR) interstitial breast brachytherapy. A novel 125I source emitting radiation in a specified direction has been developed. The directional sources contain an internal radiation shield that greatly reduces the intensity of radiation in the shielded direction. The sources have a similar dose distribution to conventional nondirectional sources on the unshielded side. The treatment plan for a patient treated with HDR interstitial brachytherapy with 192Ir (iridium) was compared with a directional 125I treatment plan using the same data set. Several dosimetric parameters are compared including target volume coverage, volume receiving 50%, 100%, and 150% of the prescription dose (V50, V100, and V150, respectively), dose homogeneity index (DHI), and the skin surface areas receiving 30%, 50%, and 80% of the prescription dose (S30, S50, and S80, respectively). The HDR and LDR prescription doses were 34 Gy in ten fractions delivered over five days and 45 Gy in 108 h, respectively. Similar and excellent target volume coverage was achieved by both directional LDR and HDR plans (99.2% and 97.5%, respectively). For a 170 cm3 target volume, the dosimetric parameters were similar for LDR and HDR: DHI was 0.82 in both cases, V100 was 214.4 cm3 and 225.7 cm3, and V150 was 39.1 cm3 and 40.4 cm3, respectively. However, with directional LDR, significant reductions in skin dose were achieved: S30 was reduced from 100.6 to 62.5 cm2, S50 from 50.6 to 16.1 cm2, and S80 from 2 cm2 to zero. The reduction in V50 for the whole breast was more than 100 cm3 (386.1 cm3 for LDR versus 489.2 cm3 for HDR). In this case study, compared with HDR, directional interstitial LDR 125I sources allow similar dose coverage to the subcutaneous target volume while lowering the skin dose due to a more conformal dose distribution and quicker falloff beyond the target. The improved dose distribution provided by directional interstitial brachytherapy might enable partial breast treatment to tumors closer to the skin or chest wall or in relatively small breasts.

3D printer generated thorax phantom with mobile tumor for radiation dosimetry.

This article describes the design, construction, and properties of an anthropomorphic thorax phantom with a moving surrogate tumor. This novel phantom permits detection of dose both inside and outside a moving tumor and within the substitute lung tissue material. A 3D printer generated the thorax shell composed of a chest wall, spinal column, and posterior regions of the phantom. Images of a computed tomography scan of the thorax from a patient with lung cancer provided the template for the 3D printing. The plastic phantom is segmented into two materials representing the muscle and bones, and its geometry closely matches a patient. A surrogate spherical plastic tumor controlled by a 3D linear stage simulates a lung tumors trajectory during normal breathing. Sawdust emulates the lung tissue in terms of average and distribution in Hounsfield numbers. The sawdust also provides a forgiving medium that permits tumor motion and sandwiching of radiochromic film inside the mobile surrogate plastic tumor for dosimetry. A custom cork casing shields the film and tumor and eliminates film bending during extended scans. The phantom, lung tissue surrogate, and radiochromic film are exposed to a seven field plan based on an ECLIPSE plan for 6 MV photons from a Trilogy machine delivering 230 cGy to the isocenter. The dose collected in a sagittal plane is compared to the calculated plan. Gamma analysis finds 8.8% and 5.5% gamma failure rates for measurements of large amplitude trajectory and static measurements relative to the large amplitude plan, respectively. These particular gamma analysis results were achieved using parameters of 3% dose and 3 mm, for regions receiving doses >150 cGy. The plan assumes a stationary detection grid unlike the moving radiochromic film and tissues. This difference was experimentally observed and motivated calculated dose distributions that incorporated the phase of the tumor periodic motion. These calculations modestly improve agreement between the measured and intended doses.

Beam-specific planning target volumes incorporating 4D CT for pencil beam scanning proton therapy of thoracic tumors.

The purpose of this study is to determine whether organ sparing and target coverage can be simultaneously maintained for pencil beam scanning (PBS) proton therapy treatment of thoracic tumors in the presence of motion, stopping power uncertainties, and patient setup variations. Ten consecutive patients that were previously treated with proton therapy to 66.6/1.8 Gy (RBE) using double scattering (DS) were replanned with PBS. Minimum and maximum intensity images from 4D CT were used to introduce flexible smearing in the determination of the beam specific PTV (BSPTV). Datasets from eight 4D CT phases, using ±3% uncertainty in stopping power and ±3 mm uncertainty in patient setup in each direction, were used to create 8×12×10=960 PBS plans for the evaluation of 10 patients. Plans were normalized to provide identical coverage between DS and PBS. The average lung V20, V5, and mean doses were reduced from 29.0%, 35.0%, and 16.4 Gy with DS to 24.6%, 30.6%, and 14.1 Gy with PBS, respectively. The average heart V30 and V45 were reduced from 10.4% and 7.5% in DS to 8.1% and 5.4% for PBS, respectively. Furthermore, the maximum spinal cord, esophagus, and heart doses were decreased from 37.1 Gy, 71.7 Gy, and 69.2 Gy with DS to 31.3 Gy, 67.9 Gy, and 64.6 Gy with PBS. The conformity index (CI), homogeneity index (HI), and global maximal dose were improved from 3.2, 0.08, 77.4 Gy with DS to 2.8, 0.04, and 72.1 Gy with PBS. All differences are statistically significant, with p-values <0.05, with the exception of the heart V45 (p=0.146). PBS with BSPTV achieves better organ sparing and improves target coverage using a repainting method for the treatment of thoracic tumors. Incorporating motion-related uncertainties is essential. PACS number: 87.55.D.The purpose of this study is to determine whether organ sparing and target coverage can be simultaneously maintained for pencil beam scanning (PBS) proton therapy treatment of thoracic tumors in the presence of motion, stopping power uncertainties, and patient setup variations. Ten consecutive patients that were previously treated with proton therapy to 66.6/1.8 Gy (RBE) using double scattering (DS) were replanned with PBS. Minimum and maximum intensity images from 4D CT were used to introduce flexible smearing in the determination of the beam specific PTV (BSPTV). Datasets from eight 4D CT phases, using ±3% uncertainty in stopping power and ±3 mm uncertainty in patient setup in each direction, were used to create 8×12×10=960 PBS plans for the evaluation of 10 patients. Plans were normalized to provide identical coverage between DS and PBS. The average lung V20, V5, and mean doses were reduced from 29.0%, 35.0%, and 16.4 Gy with DS to 24.6%, 30.6%, and 14.1 Gy with PBS, respectively. The average heart V30 and V45 were reduced from 10.4% and 7.5% in DS to 8.1% and 5.4% for PBS, respectively. Furthermore, the maximum spinal cord, esophagus, and heart doses were decreased from 37.1 Gy, 71.7 Gy, and 69.2 Gy with DS to 31.3 Gy, 67.9 Gy, and 64.6 Gy with PBS. The conformity index (CI), homogeneity index (HI), and global maximal dose were improved from 3.2, 0.08, 77.4 Gy with DS to 2.8, 0.04, and 72.1 Gy with PBS. All differences are statistically significant, with p‐values <0.05, with the exception of the heart V45 (p=0.146). PBS with BSPTV achieves better organ sparing and improves target coverage using a repainting method for the treatment of thoracic tumors. Incorporating motion‐related uncertainties is essential. PACS number: 87.55.D

Development and Clinical Implementation of a Universal Bolus to Maintain Spot Size During Delivery of Base of Skull Pencil Beam Scanning Proton Therapy

PURPOSE To report on a universal bolus (UB) designed to replace the range shifter (RS); the UB allows the treatment of shallow tumors while keeping the pencil beam scanning (PBS) spot size small. METHODS AND MATERIALS Ten patients with brain cancers treated from 2010 to 2011 were planned using the PBS technique with bolus and the RS. In-air spot sizes of the pencil beam were measured and compared for 4 conditions (open field, with RS, and with UB at 2- and 8-cm air gap) in isocentric geometry. The UB was applied in our clinic to treat brain tumors, and the plans with UB were compared with the plans with RS. RESULTS A UB of 5.5 cm water equivalent thickness was found to meet the needs of the majority of patients. By using the UB, the PBS spot sizes are similar with the open beam (P>.1). The heterogeneity index was found to be approximately 10% lower for the UB plans than for the RS plans. The coverage for plans with UB is more conformal than for plans with RS; the largest increase in sparing is usually for peripheral organs at risk. CONCLUSIONS The integrity of the physical properties of the PBS beam can be maintained using a UB that allows for highly conformal PBS treatment design, even in a simple geometry of the fixed beam line when noncoplanar beams are used.