Wensha Yang

Chest Wall Volume Receiving >30 Gy Predicts Risk of Severe Pain and/or Rib Fracture After Lung Stereotactic Body Radiotherapy

PURPOSE To identify the dose-volume parameters that predict the risk of chest wall (CW) pain and/or rib fracture after lung stereotactic body radiotherapy. METHODS AND MATERIALS From a combined, larger multi-institution experience, 60 consecutive patients treated with three to five fractions of stereotactic body radiotherapy for primary or metastatic peripheral lung lesions were reviewed. CW pain was assessed using the Common Toxicity Criteria for pain. Peripheral lung lesions were defined as those located within 2.5 cm of the CW. A minimal point dose of 20 Gy to the CW was required. The CW volume receiving >or=20, >or=30, >or=40, >or=50, and >or=60 Gy was determined and related to the risk of CW toxicity. RESULTS Of the 60 patients, 17 experienced Grade 3 CW pain and five rib fractures. The median interval to the onset of severe pain and/or fracture was 7.1 months. The risk of CW toxicity was fitted to the median effective concentration dose-response model. The CW volume receiving 30 Gy best predicted the risk of severe CW pain and/or rib fracture (R(2) = 0.9552). A volume threshold of 30 cm(3) was observed before severe pain and/or rib fracture was reported. A 30% risk of developing severe CW toxicity correlated with a CW volume of 35 cm(3) receiving 30 Gy. CONCLUSION The development of CW toxicity is clinically relevant, and the CW should be considered an organ at risk in treatment planning. The CW volume receiving 30 Gy in three to five fractions should be limited to <30 cm(3), if possible, to reduce the risk of toxicity without compromising tumor coverage.

Comparison of Elekta VMAT with helical tomotherapy and fixed field IMRT: plan quality, delivery efficiency and accuracy.

PURPOSE Helical tomotherapy (HT) and volumetric modulated arc therapy (VMAT) are arc-based approaches to IMRT delivery. The objective of this study is to compare VMAT to both HT and fixed field IMRT in terms of plan quality, delivery efficiency, and accuracy. METHODS Eighteen cases including six prostate, six head-and-neck, and six lung cases were selected for this study. IMRT plans were developed using direct machine parameter optimization in the Pinnacle3 treatment planning system. HT plans were developed using a Hi-Art II planning station. VMAT plans were generated using both the Pinnacle3 SmartArc IMRT module and a home-grown arc sequencing algorithm. VMAT and HT plans were delivered using Elektas PreciseBeam VMAT linac control system (Elekta AB, Stockholm, Sweden) and a TomoTherapy Hi-Art II system (TomoTherapy Inc., Madison, WI), respectively. Treatment plan quality assurance (QA) for VMAT was performed using the IBA MatriXX system while an ion chamber and films were used for HT plan QA. RESULTS The results demonstrate that both VMAT and HT are capable of providing more uniform target doses and improved normal tissue sparing as compared with fixed field IMRT. In terms of delivery efficiency, VMAT plan deliveries on average took 2.2 min for prostate and lung cases and 4.6 min for head-and-neck cases. These values increased to 4.7 and 7.0 min for HT plans. CONCLUSIONS Both VMAT and HT plans can be delivered accurately based on their own QA standards. Overall, VMAT was able to provide approximately a 40% reduction in treatment time while maintaining comparable plan quality to that of HT.

Computed tomography-based anatomic assessment overestimates local tumor recurrence in patients with mass-like consolidation after stereotactic body radiotherapy for early-stage non-small cell lung cancer.

PURPOSE To investigate pulmonary radiologic changes after lung stereotactic body radiotherapy (SBRT), to distinguish between mass-like fibrosis and tumor recurrence. METHODS AND MATERIALS Eighty consecutive patients treated with 3- to 5-fraction SBRT for early-stage peripheral non-small cell lung cancer with a minimum follow-up of 12 months were reviewed. The mean biologic equivalent dose received was 150 Gy (range, 78-180 Gy). Patients were followed with serial CT imaging every 3 months. The CT appearance of consolidation was defined as diffuse or mass-like. Progressive disease on CT was defined according to Response Evaluation Criteria in Solid Tumors 1.1. Positron emission tomography (PET) CT was used as an adjunct test. Tumor recurrence was defined as a standardized uptake value equal to or greater than the pretreatment value. Biopsy was used to further assess consolidation in select patients. RESULTS Median follow-up was 24 months (range, 12.0-36.0 months). Abnormal mass-like consolidation was identified in 44 patients (55%), whereas diffuse consolidation was identified in 12 patients (15%), at a median time from end of treatment of 10.3 months and 11.5 months, respectively. Tumor recurrence was found in 35 of 44 patients with mass-like consolidation using CT alone. Combined with PET, 10 of the 44 patients had tumor recurrence. Tumor size (hazard ratio 1.12, P=.05) and time to consolidation (hazard ratio 0.622, P=.03) were predictors for tumor recurrence. Three consecutive increases in volume and increasing volume at 12 months after treatment in mass-like consolidation were highly specific for tumor recurrence (100% and 80%, respectively). Patients with diffuse consolidation were more likely to develop grade ≥ 2 pneumonitis (odds ratio 26.5, P=.02) than those with mass-like consolidation (odds ratio 0.42, P=.07). CONCLUSION Incorporating the kinetics of mass-like consolidation and PET to the current criteria for evaluating posttreatment response will increase the likelihood of correctly identifying patients with progressive disease after lung SBRT.

Four-dimensional MRI using three-dimensional radial sampling with respiratory self-gating to characterize temporal phase-resolved respiratory motion in the abdomen

To develop a four‐dimensional MRI (4D‐MRI) technique to characterize the average respiratory tumor motion for abdominal radiotherapy planning.

Semiconductor nanoparticles as energy mediators for photosensitizer-enhanced radiotherapy.

PURPOSE It has been proposed that quantum dots (QDs) can be used to excite conjugated photosensitizers and produce cytotoxic singlet oxygen. To study the potential of using such a conjugate synergistically with radiotherapy to enhance cell killing, we investigated the energy transfer from megavoltage (MV) X-rays to a photosensitizer using QDs as the mediator and quantitated the enhancement in cell killing. METHODS AND MATERIALS The photon emission efficiency of QDs on excitation by 6-MV X-rays was measured using dose rates of 100-600 cGy/min. A QD-Photofrin conjugate was synthesized by formation of an amide bond. The role of Förster resonance energy transfer in the energy transferred to the Photofrin was determined by measuring the degree of quenching at different QD/Photofrin molar ratios. The enhancement of H460 human lung carcinoma cell killing by radiation in the presence of the conjugates was studied using a clonogenic survival assay. RESULTS The number of visible photons generated from QDs excited by 6-MV X-rays was linearly proportional to the radiation dose rate. The Förster resonance energy transfer efficiency approached 100% as the number of Photofrin molecules conjugated to the QDs increased. The combination of the conjugate with radiation resulted in significantly lower H460 cell survival in clonogenic assays compared with radiation alone. CONCLUSION The novel QD-Photofrin conjugate shows promise as a mediator for enhanced cell killing through a linear and highly efficient energy transfer from X-rays to Photofrin.

Tumor cell apoptosis induced by nanoparticle conjugate in combination with radiation therapy

Semiconductor nanoparticles conjugated to photosensitizers have been shown to increase tumor cell death with ionizing radiation but the mechanism, particularly the role of photodynamic therapy in the process, was unknown. We used a molecular probe to measure production of (1)O(2) to quantify the component of photodynamic cell-killing in an in vitro system. The intracellular distribution of the nanoparticle conjugate (NC) was determined by the co-localization of nanoparticles and the lysotracker. Induction of apoptosis was measured by the TUNEL assay and western blot analysis of the cleaved caspase-3. As a result, dose-dependent (1)O(2) production was observed with 48 nm NC after irradiating with 6 MV x-rays. A high geometrical coincidence between the fluorescence emission of the nanoparticle and lysotracker was observed using confocal microscopy. Finally, apoptosis, as indicated by the TUNEL stain and cleavage of the caspase-3, was observed in cells treated by both the NC and 6 Gy of radiation but not in cells treated with radiation alone. In conclusion, the cell death induced by the NC in combination with radiation is consistent with a supra-additive effect to radiation-or NC-alone-killing and is mediated by an NC-induced photodynamic therapy mechanism, which is distinctly different from that for radiation-killing alone. By providing a second distinct cell-killing mechanism, this nanoparticle conjugate has great promise as a targeted physical radiosensitizer aimed at overcoming radioresistant tumor clonogens or/and reducing normal tissue toxicity by using a lower ionizing radiation dose.

3D DOSE VERIFICATION USING TOMOTHERAPY CT DETECTOR ARRAY

PURPOSE To evaluate a three-dimensional dose verification method based on the exit dose using the onboard detector of tomotherapy. METHODS AND MATERIALS The study included 347 treatment fractions from 24 patients, including 10 prostate, 5 head and neck (HN), and 9 spinal stereotactic body radiation therapy (SBRT) cases. Detector sonograms were retrieved and back-projected to calculate entrance fluence, which was then forward-projected on the CT images to calculate the verification dose, which was compared with ion chamber and film measurement in the QA plans and with the planning dose in patient plans. RESULTS Root mean square (RMS) errors of 2.0%, 2.2%, and 2.0% were observed comparing the dose verification (DV) and the ion chamber measured point dose in the phantom plans for HN, prostate, and spinal SBRT patients, respectively. When cumulative dose in the entire treatment is considered, for HN patients, the error of the mean dose to the planning target volume (PTV) varied from 1.47% to 5.62% with a RMS error of 3.55%. For prostate patients, the error of the mean dose to the prostate target volume varied from -5.11% to 3.29%, with a RMS error of 2.49%. The RMS error of maximum doses to the bladder and the rectum were 2.34% (-4.17% to 2.61%) and 2.64% (-4.54% to 3.94%), respectively. For the nine spinal SBRT patients, the RMS error of the minimum dose to the PTV was 2.43% (-5.39% to 2.48%). The RMS error of maximum dose to the spinal cord was 1.05% (-2.86% to 0.89%). CONCLUSIONS An excellent agreement was observed between the measurement and the verification dose. In the patient treatments, the agreement in doses to the majority of PTVs and organs at risk is within 5% for the cumulative treatment course doses. The dosimetric error strongly depends on the error in multileaf collimator leaf opening time with a sensitivity correlating to the gantry rotation period.

Four-Dimensional Magnetic Resonance Imaging With 3-Dimensional Radial Sampling and Self-Gating-Based K-Space Sorting: Early Clinical Experience on Pancreatic Cancer Patients.

PURPOSE To apply a novel self-gating k-space sorted 4-dimensional MRI (SG-KS-4D-MRI) method to overcome limitations due to anisotropic resolution and rebinning artifacts and to monitor pancreatic tumor motion. METHODS AND MATERIALS Ten patients were imaged using 4D-CT, cine 2-dimensional MRI (2D-MRI), and the SG-KS-4D-MRI, which is a spoiled gradient recalled echo sequence with 3-dimensional radial-sampling k-space projections and 1-dimensional projection-based self-gating. Tumor volumes were defined on all phases in both 4D-MRI and 4D-CT and then compared. RESULTS An isotropic resolution of 1.56 mm was achieved in the SG-KS-4D-MRI images, which showed superior soft-tissue contrast to 4D-CT and appeared to be free of stitching artifacts. The tumor motion trajectory cross-correlations (mean ± SD) between SG-KS-4D-MRI and cine 2D-MRI in superior-inferior, anterior-posterior, and medial-lateral directions were 0.93 ± 0.03, 0.83 ± 0.10, and 0.74 ± 0.18, respectively. The tumor motion trajectories cross-correlations between SG-KS-4D-MRI and 4D-CT in superior-inferior, anterior-posterior, and medial-lateral directions were 0.91 ± 0.06, 0.72 ± 0.16, and 0.44 ± 0.24, respectively. The average standard deviation of gross tumor volume calculated from the 10 breathing phases was 0.81 cm(3) and 1.02 cm(3) for SG-KS-4D-MRI and 4D-CT, respectively (P=.012). CONCLUSIONS A novel SG-KS-4D-MRI acquisition method capable of reconstructing rebinning artifact-free, high-resolution 4D-MRI images was used to quantify pancreas tumor motion. The resultant pancreatic tumor motion trajectories agreed well with 2D-cine-MRI and 4D-CT. The pancreatic tumor volumes shown in the different phases for the SG-KS-4D-MRI were statistically significantly more consistent than those in the 4D-CT.

Radiation therapy of post-mastectomy patients with positive nodes using fixed beam tomotherapy

PURPOSES To develop an optimized dosimetric class solution for post-mastectomy irradiation for fixed beam tomotherapy (FBT). METHODS AND MATERIALS CT simulation scans from 10 post-mastectomy patients were used to generate plans with planning target volumes (PTVs) that included the chest wall, axillary nodes and supraclavical nodes using FBT and helical tomotherapy (HT) with 3D and IMRT modes and the resultant dosimetry was compared to conventional IMRT. FBT IMRT plans were analyzed with both 4 (4FBT) and 11-field (11FBT) plans. Important organs at risk (OARs) included the heart, ipsilateral and contralateral lungs, esophagus and contralateral breast. In all plans, the spinal cord and contralateral lung were completely blocked while the heart and ipsilateral lung were directionally blocked. Doses to the contralateral breast were minimized. Each plan was evaluated for its delivery time, percentile volume of lung receiving x Gy (V(x)) and dose received by x percent volume (D(x)). D(1) and D(5) were used to measure the maximum dose to the OAR or PTV, D(95) and D(99) were used to measure the minimal dose to the PTV. RESULTS Compared to the conventional IMRT technique, HT IMRT, 11FBT IMRT and 11FBT 3D significantly reduced the D(1) of the heart in cases of left-sided tumors by 13%, 41% and 36%, and the V(10) of ipsilateral lung in all cases by 26%, 49% and 46%, respectively. A close to 90% reduction in the contralateral breast dose was also observed with the 11FBT plans. Target dose homogeneity of 11FBT 3D plans is inferior to that of the HT and conventional IMRT plans but the treatment delivery time, 7.59 min, was significantly shorter by 3 min. 4FBT IMRT resulted in clinically unacceptable heterogeneity with high dose regions in both the PTV and normal tissue. CONCLUSIONS A class solution based on an 11 beam configuration was established to optimize the dosimetry of fixed beam tomotherapy planning for post-mastectomy patients. The 11FBT plans were deliverable in clinically efficient treatment times.

Tumor cell survival dependence on helical tomotherapy, continuous arc and segmented dose delivery

The temporal pattern of radiation delivery has been shown to influence the tumor cell survival fractions for the same radiation dose. To study the effect more specifically for state of the art rotational radiation delivery modalities, 2 Gy of radiation dose was delivered to H460 lung carcinoma, PC3 prostate cancer cells and MCF-7 breast tumor cells by helical tomotherapy (HT), seven-field LINAC (7F), and continuous dose delivery (CDD) over 2 min that simulates volumetric rotational arc therapy. Cell survival was measured by the clonogenic assay. The number of viable H460 cell colonies was 23.2 +/- 14.4% and 27.7 +/- 15.6% lower when irradiated by CDD compared with HT and 7F, respectively, and the corresponding values were 36.8 +/- 18.9% and 35.3 +/- 18.9% lower for MCF7 cells (p < 0.01). The survival of PC3 was also lower when irradiated by CDD than by HT or 7F but the difference was not as significant (p = 0.06 and 0.04, respectively). The higher survival fraction from HT delivery was unexpected because 90% of the 2 Gy was delivered in less than 1 min at a significantly higher dose rate than the other two delivery techniques. The results suggest that continuous dose delivery at a constant dose rate results in superior in vitro tumor cell killing compared with prolonged, segmented or variable dose rate delivery.