2D IMRT QA passing rate dependency on coronal plane.

Intensity modulated radiation therapy (IMRT) delivery involves a complex series of beam angles and multileaf collimator (MLC) arrangements, requiring quality assurance to be performed to validate delivery before treatment. The purpose of this work is to investigate the effect of dose gradient on quality assurance (QA) passing rate. Many (n = 40) IMRT plans were delivered and measured using a 2D planar array of ion chambers; additionally, eleven plans were measured at several coronal planes. For each measurement, dose gradient was assessed using a number of metrics and passing rate assessed at both 3%/3 mm and 3%/2 mm criteria. The passing rates of the various IMRT plans were shown to be generally correlated to gradient, with an average distance correlation of 0.54 ± 0.04 for the lateral dose gradient. The passing rate for an individual plan was shown to vary with coronal slice, though the correlation to dose gradient was not predictable. Even though the passing rate was strongly related to dose gradient for many of the plans, the signs of the correlations were not always negative, as hypothesized. The coronal plane at which QA is performed affects passing rate, though dose gradient may not easily be used to predict slices at which passing rate is higher.

A new target localization method for image-guided radiation therapy of prostate cancer.

In imaged-guided radiation therapy (IGRT), target localization is usually done with rigid-body registration based on anatomy matching. Problems arise when the target volume can only be matched partially due to inter-fractional organ motion and deformation, resulting in deteriorated target coverage and critical structure sparing. A new target localization method is investigated in which the treatment target volume is aligned with the prescription isodose surface. Our study included 15 prostate patients previously treated with intensity-modulated radiation therapy (IMRT). Patient setup and target localization were performed using a CT-on-rails system before and after the IMRT treatment. IMRT plans were generated on the original simulation CTs (15) and the same MUs and leaf sequences were used to compute the dose distributions on post-treatment CTs (98) with the isocenter adjustments based on either anatomical structure matching or prescription isodose surface alignment. When patients were aligned with the traditional anatomy matching method, the dose to 95% of the CTV, D95, received 74.0 - 77.6 Gy and the minimum CTV dose, Dmin, was 61.9 - 71.6 Gy, respectively, in the cumulative dose distributions. The rectal dose-volume constraints were violated in 35.7% of the treatment fractions. When patients were aligned using the new localization method, the dose to 95% of the CTV, D95, received 74.0 - 78.2 Gy and the minimum CTV dose, Dmin, was 68.4 - 71.6 Gy, respectively, in the cumulative dose distributions. The rectal dose-volume constraints were violated in 17.3% of the treatment fractions. Traditional IGRT target localization based on anatomy matching is effective for population-based PTV margins but not ideal for those patients with large inter-fractional prostate rotation/deformation due to large rectal and bladder volume variation. The new method using the prescription isodose surface to align the target volume could improve the target coverage and rectal sparing for these patients, which can be implemented clinically to improve target dose delivery accuracy.

Therapeutic effects of in-vivo radiodynamic therapy (RDT) for lung cancer treatment: a combination of 15MV photons and 5-aminolevulinic acid (5-ALA).

Objective.Radiodynamic therapy (RDT) uses high-energy photon beams instead of visible/near-infrared light to treat deep-seated tumors that photodynamic therapy cannot achieve due to the low penetration depth of laser beams. The purpose of this study is to investigate the therapeutic effect of RDT with 15 MV photon beams combined with 5-aminolevulinic acid (5-ALA) using a mouse model.Approach.A subcutaneous C57BL/6 mouse model of KP1 small-cell lung cancer cell line was used. The tumors (N = 120) were randomized into four groups to observe individual and synergistic effects of 5-ALA and radiation treatment: control (untreated, N = 42), radiation treatment (RT) only (N = 20), 5-ALA only (N = 20), and RDT (N = 38). For the RT only and RDT groups, 4 Gy in a single fraction was delivered to the tumors using 15 MV photons. For the 5-ALA only and RDT groups, 5-ALA was injected at a dose of 100 mg kg-1by tail-vein 4 h prior to RT. The tumor response was assessed by monitoring tumor growth using 1.5 T MR, maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) using [18F]FDG PET/CT, and animal survival.Main results.RDT achieved a statistically significant delay in tumor growth by 52.1%, 48.1%, and 57.9% 7 days post-treatment compared to 5-ALA only, RT only, and control group (P < 0.001), respectively. There were no significant differences in tumor growth between 5-ALA only and RT only groups. An additional 38.5%-40.9% decrease in tumor growth was observed, showing a synergistic effect with RDT. Furthermore, RDT significantly decreased [18F]FDG uptakes in SUVmaxand TLG 7 days post-treatment by 47.4% and 66.5% (P < 0.001), respectively. RDT mice survived the longest of all treatment groups.Significance.RDT with 15 MV photons and 5-ALA resulted in greater tumor control compared to the control and other treatment groups. A significant synergistic effect was also observed with RDT. These preliminary results demonstrate an effective cancer treatment modality.

Evaluating suggested stricter gamma criteria for linac-based patient-specific delivery QA in the conventional and SBRT environments.

PURPOSE: To evaluate AAPM TG-218 recommended tolerances for IMRT QA for conventional and SBRT delivery. METHODS: QA analysis was repeated for 150 IMRT/VMAT patients with varying gamma criteria. True composite delivery was utilized, corrected for detector and output variation. Universal tolerance (TLuniv) and action limits (ALuniv) were compared with statistical process control (SPC) TLSPC and ALSPC values. Analysis was repeated as a function of plan complexity for 250 non-stereotactic body radiotherapy (SBRT) VMAT patients at 3%/2mm and a threshold of 10% and for 75 SBRT VMAT patients at 2%/2 mm and a threshold of 50% with results plotted as a function of PTV volume. Regions of failure were dose-scaled on the planning CT data sets based on delivery results. RESULTS: The IMRT/VMAT TLSPC and ALSPC for gamma criteria of 3%/3 mm were 96.5% and 95.6% and for 3%/2 mm were 91.2% and 89.2%, respectively. Correlation with plan complexity for conventional fractionation VMAT was "low" for all sites with pelvis having the highest r value at -0.35. The equivalent SBRT PTV diameter ranged from 2.0 cm to 5.6 cm. Negative low correlation was found for 38 of 75 VMAT cases below ALuniv. CONCLUSIONS: The ALuniv and ALSPC are similar for 3%/2 mm. However, our 5% failure rate for ALuniv, may result in treatment start delays approximately 2 times/month, given 40 new cases/month. VMAT QA failure at stricter criteria did not correlate strongly with plan complexity. Site-specific action limits vary less than 3% from the average. SBRT QA results do not strongly correlate with target size over the range studied.

Pulsed low dose-rate radiotherapy: radiobiology and dosimetry.

Pulsed low dose-rate radiotherapy (PLDR) relies on two radiobiological findings, the hyper-radiosensitivity of tumor cells at small doses and the reduced normal tissue toxicity at low dose rates. This is achieved by delivering the daily radiation dose of 2 Gy in 10 sub-fractions (pulses) with a 3 min time interval, resulting in an effective low dose rate of 0.067 Gy min-1.In vitrocell studies andin vivoanimal experiments demonstrated the therapeutic potential of PLDR treatments and provided useful preclinical data. Various treatment optimization strategies and delivery techniques have been developed for PLDR on existing linear accelerators. Preliminary results from early clinical studies have shown favorable outcomes for various treatment sites especially for recurrent cancers. This paper reviews the experimental findings of PLDR and dosimetric requirements for PLDR treatment planning and delivery, and summarizes major clinical studies on PLDR cancer treatments.

Dosimetric evaluation of image-guided radiation therapy for prostate cancer.

The aim of this study was to investigate the dosimetric accuracy of imaged-guided radiation therapy for prostate patients using the in-room computed tomography (CT) target localization technique. A Siemens CT-on-rails system was used for patient setup and target localization for intensity-modulated radiation therapy (IMRT) of prostate cancer. Fifteen previously treated prostate patients were included in this retrospective study. CT-on-Rails scans were performed before and after the IMRT treatment under local IRB approval. A total of 15 original simulation CT scans and 98 post-treatment CT scans were contoured by the same oncologist to delineate the prostate target, bladder, and rectum. IMRT plans were generated on the original simulation CTs and the same MUs and leaf sequences were used to compute the dose distributions using post-treatment CTs. Varian Velocity deformable registration was used for the summation of the fractional doses and the cumulative doses were compared with the planned doses. For the 15 patients investigated, the mean isocenter shift was up to 4.0 mm in the left-right direction, 5.9 mm in the anterior-posterior direction and 5.6 mm in the superior-inferior direction due to interfractional organ motion. The mean rectal volume varied from 0.6 to 1.73 times and the mean bladder volume varied from 0.59 to 3.65 times between simulation and the end of treatment. The prescription dose to 95% of the PTV, Dp, was set to 76 Gy for all treatment plans. The dose to 95% of the clinical treatment volume (CTV), D95, was 74.0 to 77.6 Gy and the minimum CTV dose, Dmin, was 61.0 to 71.6 Gy, respectively, in the cumulative dose distributions. Detailed analyses showed that 7.1% of the treatment fractions had cold spots (< 85% of Dp) in the peripheral CTV, leading to Dmin < 64 Gy in the cumulative dose distributions for 4 patients. The rectal dose-volume constraints were violated in 35.7% of the treatment fractions while the bladder dose was much improved in 82.7% of the treatment fractions. The current IGRT procedure for patient setup and target localization using rigid-body registration based on contour/anatomy matching is effective for population-based PTV margins. For a small group of patients, specific PTV margins and/or real-time target monitoring/tracking will be necessary due to significant prostate deformation/rotation caused by inter- and intrafractional bladder and rectal volume variation.

Pelvic Reirradiation Utilizing Pulsed Low-dose Rate Radiation Therapy.

Pulsed low-dose rate radiation therapy has been shown to reduce normal tissue damage while decreasing DNA damage repair in tumor cells. In a cohort of patients treated with palliative or definitive pelvic reirradiation using pulsed low-dose rate radiation therapy, we observed substantial local control and low rates of toxicity.

Time and frequency to observe fiducial markers in MLC-modulated fields during prostate IMRT/VMAT beam delivery.

OBJECTIVE: This work investigates the time and frequency to observe fiducial markers in MLC-modulated fields during intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) beam delivery for real-time prostate localization. METHODS: Thirty seven prostate patients treated with IMRT or VMAT were included in this retrospective study. DRR images were generated for all MLC segments/control points using the TPS. The MLC leaf pattern of each control point was overlaid on the DRR, and the number of fiducials within the MLC opening was analyzed. EPID images of fiducials in a pelvic phantom were obtained to demonstrate the fiducial visibility during modulated beam delivery. RESULTS: Gold fiducials were visible on EPID images. The probability of seeing a number of fiducials within the MLC opening was analyzed. At least one fiducial was visible during 42 ± 2% and 52 ± 2% beam-on time for IMRT of the prostate with and without lymph nodes, and during 81 ± 4% and 80 ± 5% beam-on time for VMAT of the prostate with and without lymph nodes, respectively. The mean time interval to observe at least one fiducial was 8.4 ± 0.7 and 5.9 ± 0.5 s for IMRT of the prostate with and without the lymph nodes, respectively, and 1.6 ± 0.1 s for VMAT prostate patients. The estimated potential dosimetric uncertainty was 7% and 2% for IMRT and VMAT, respectively. CONCLUSIONS: Our results demonstrated that the time and frequency to observe fiducial markers in MLC-modulated fields during IMRT/VMAT beam delivery were adequate for real-time prostate localization. The beam's eye view fiducial positions could be used for intrafractional target monitoring and motion correction in prostate radiotherapy.

Radiodynamic therapy using 15-MV radiation combined with 5-aminolevulinic acid and carbamide peroxide for prostate cancer in vivo.

Photodynamic therapy has been clinically proven to be effective, but its effect is limited to relatively shallow tumors because of its use of visible light. Radiodynamic therapy (RDT) has therefore been investigated as a means to treat deep-seated tumors. In this study, the treatment effect of a novel form of RDT consisting of radiation combined with 5-aminolevulinic acid (5-ALA) and carbamide peroxide was investigated using a mouse model. Male nude mice were injected bilaterally and subcutaneously with human prostate cancer (PC-3) cells and randomized into 8 treatment groups, consisting of various combinations of 15-MV radiotherapy (RT), 5-ALA, and carbamide peroxide. The treatment effect of a single fraction of treatment was measured by calculating tumor growth delay, monitored using weekly MR scans. The ability of the drugs to be delivered to the tumors was qualitatively measured using 18 F-FDG PET/CT scans. RDT was shown to significantly delay the tumor growth for the mouse model and tumor cell line investigated in this work. Tumors treated with RDT showed a decrease in tumor growth of 24 ± 9% and 21 ± 8% at one and two weeks post-treatment, respectively. Peroxide and 5-ALA did not contribute significantly to tumor growth delay when administered alone or separately with RT. Blood perfusion was shown to be able to deliver agents to the tumors investigated in this work, although uptake of 18 F-FDG was shown to be non-uniform.

Evaluation of the combined use of two different respiratory monitoring systems for 4D CT simulation and gated treatment.

PURPOSE: Two different respiratory monitoring systems (Varian's Real-Time Position Management (RPM) System and Siemens' ANZAI belt Respiratory Gating System) are compared in the context of respiratory signals and 4D CT images that are accordingly reconstructed. This study aims to evaluate the feasibility of combined use of RPM and ANZAI systems for 4DCT simulation and gated radiotherapy treatment, respectively. METHODS: The RPM infrared reflecting marker and the ANZAI belt pressure sensor were both placed on the patient's abdomen during 4DCT scans. The respiratory signal collected by the two systems was synchronized. Fifteen patients were enrolled for respiratory signal collection and analysis. The discrepancies between the RPM and ANZAI traces can be characterized by phase shift and shape distortion. To reveal the impact of the changes in respiratory signals on 4D images, two sets of 4D images based on the same patient's raw data were reconstructed using the RPM and ANZAI data for phase sorting, respectively. The volume of whole lung and the position of diaphragm apex were measured and compared for each respiratory phase. RESULTS: The mean phase shift was measured as 0.2 ± 0.1 s averaged over 15 patients. The shape of the breathing trace was found to be in disagreement. For all the patients, the ANZAI trace had a steeper falloff in exhalation than RPM. The inhalation curve, however, was matched for nine patients, steeper in ANZAI for five patients and steeper in RPM for one patient. For 4D image comparison, the difference in whole-lung volume was about -4% to +4% and the difference in diaphragm position was about -5 mm to +4 mm, compared in each individual phase and averaged over seven patients. CONCLUSIONS: Combined use of one system for 4D CT simulation and the other for gated treatment should be avoided as the resultant gating window would not fully match with each other due to the remarkable discrepancy in breathing traces acquired by the two different surrogate systems.

Local Control and Toxicity of External Beam Reirradiation With a Pulsed Low-dose-rate Technique.

PURPOSE: To evaluate the efficacy and toxicity of external beam reirradiation using a pulsed low-dose-rate (PLDR) technique. METHODS AND MATERIALS: We evaluated patients treated with PLDR reirradiation from 2009 to 2016 at a single institution. Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0, and local control was assessed using the Response Evaluation Criteria In Solid Tumors, version 1.1. On univariate analysis (UVA), the χ2 and Fisher exact tests were used to assess the toxicity outcomes. Competing risk analysis using cumulative incidence function estimates were used to assess local progression. RESULTS: A total of 39 patients were treated to 41 disease sites with PLDR reirradiation. These patients had a median follow-up time of 8.8 months (range 0.5-64.7). The targets were the thorax, abdomen, and pelvis, including 36 symptomatic sites. The median interval from the first radiation course and reirradiation was 26.2 months; the median dose of the first and second course of radiation was 50.4 Gy and 50 Gy, respectively. Five patients (13%) received concurrent systemic therapy. Of the 39 patients, 9 (23%) developed grade ≥2 acute toxicity, most commonly radiation dermatitis (5 of 9). None developed grade ≥4 acute or subacute toxicity. The only grade ≥2 late toxicity was late skin toxicity in 1 patient. On UVA, toxicity was not significantly associated with the dose of the first course of radiation or reirradiation, the interval to reirradiation, or the reirradiation site. Of the 41 disease sites treated with PLDR reirradiation, 32 had pre- and post-PLDR scans to evaluate for local control. The local progression rate was 16.5% at 6 months and 23.8% at 12 months and was not associated with the dose of reirradiation, the reirradiation site, or concurrent systemic therapy on UVA. Of the 36 symptomatic disease sites, 25 sites (69%) achieved a symptomatic response after PLDR, including 6 (17%) with complete symptomatic relief. CONCLUSION: Reirradiation with PLDR is effective and well-tolerated. The risk of late toxicity and the durability of local control were limited by the relatively short follow-up duration in the present cohort.

When and how to treat an IMRT patient on a second accelerator without replanning?

When a linear accelerator is unavailable for treatment, a clinical decision is imminent regarding whether a patient should be treated on a linear accelerator other than the machine the patient was scheduled on, or whether treatment should be postponed until the original Linac becomes available. This work investigates the feasibility of switching patients to different accelerators for intensity-modulated radiation therapy (IMRT). We have performed Monte Carlo simulations of photon beams from different Linac models and vendors. Prostate and head and neck (H&N) treatment plans for Siemens Primus, Primart, and Varian 21EX accelerators are studied in this work. Dose distributions for given plans are recalculated using different beam data with the same nominal energy from different Linacs. We have compared dose-volume histograms (DVHs) and the maximum, the minimum, and the mean doses to the target and critical structures because of switching accelerators. In the process of switching a treatment plan to a different accelerator, issues exist, including optimum penumbra compensation, dose distribution at the boundary of target and critical structures, and multileaf collimator (MLC) leaf-width effects, which need to be considered and verified with measurements. Our Monte Carlo simulation results confirm that, for the cases we tested, the dose received by 95% of the planning target volume differs by 0.2% to 1.5% between Siemens Primus and Varian 21EX Linacs. The discrepancy is within our clinical acceptance criteria of 3% for IMRT treatments. In making the final decision on whether to switch machines or not, the tumor control probabilities (TCPs) based on a linear-quadratic model are compared. Based on the analyses performed in this work, it is therapeutically more beneficial to switch a patient to a different machine than to postpone a treatment until the original machine is available, especially for fast-growing tumors such as H&N cancers.

Induction chemotherapy followed by concurrent chemoradiation and nimotuzumab for locoregionally advanced nasopharyngeal carcinoma: preliminary results from a phase II clinical trial.

Overexpression of epidermal growth factor receptor can be found in more than 80% of patients with locoregionally advanced nasopharyngeal carcinoma and is associated with shorter survival. In this work, we evaluated the feasibility of adding nimotuzumab to chemoradiation in locoregionally advanced nasopharyngeal carcinoma. Twenty-three patients with clinically staged T3-4 or any node-positive disease were enrolled. They were scheduled to receive one cycle of induction chemotherapy followed by intensity-modulated radiotherapy, weekly administration of nimotuzumab and concurrent chemotherapy. Results showed that all patients received a full course of radiotherapy, 19(82.6%)patients completed the scheduled neoadjuvant and concurrent chemotherapy, and 22(95.7%) patients received ≥6 weeks of nimotuzumab. During the period of concurrent chemoradiation and nimotuzumab, grade 3-4 toxicities occurred in 14(60.9%) patients: 8 (34.8%) had grade 3-4 oral mucositis, 6(26.1%) had grade 3 neutropenia, and 1(4.3%) had grade 3 dermatitis. No acne-like rash was observed. With a median follow-up of 24.1 months, the 2-year progression-free survival and overall survival were 83.5% and 95.0%, respectively. In conclusion, concurrent administration of chemoradiation and nimotuzumab was well-tolerated with good compliance. Preliminary clinical outcome data appear encouraging with favorable normal tissue toxicity results comparing with historical data of concurrent chemoradiation plus cetuximab.

Investigation of the clinical potential of scattering foil free electron beams.

Electron beam therapy has been an important radiation therapy modality for many decades. Studies have been conducted recently for more efficient and advanced delivery of electron beam radiation therapy. X-ray contamination is a common problem that exists with all of the advanced electron beam therapy techniques such as Bolus Electron conformal therapy, segmented electron conformal therapy, and modulated electron arc therapy. X-ray contamination could add some limitations to the advancement and clinical utility of those electron modalities. It was previously shown in the literature that the scattering foil is one of the major accelerator parts contributing to the generation of bremsstrahlung photons. Thus, in this work we investigate the dosimetric characteristics of scattering foil free (SFF) electron beams and the feasibility of using those beams for breast cancer boosts. The SFF electron beams were modeled and simulated using the Monte Carlo method. CT scans of six previously treated breast patients were used for the treatment plan generation utilizing our in-house Monte Carlo-based treatment planning system. Electron boost plans with conventional beams and the SFF beams were generated, respectively, for all patients. A significant reduction of the photon component was observed with the removal of the primary scattering foil for beam energies higher than 12 MeV. Flatness was greatly affected but the difference in flatness between conventional and SFF beams was much reduced for small cone sizes, which were often used clinically for breast boosts. It was found that the SFF electron beams could deliver high-quality dose distributions as conventional electron beams for boost treatments of the breast with an added advantage of a further reduced dose to the lung and the heart.

Acute oral mucositis in nasopharyngeal carcinoma patients treated with radiotherapy: association with genetic polymorphism in DNA DSB repair genes.

PURPOSE: The aim of this study was to investigate the association between polymorphic variants of DNA repair genes with the susceptibility of acute oral mucositis (OM) in nasopharyngeal carcinoma (NPC) patients treated with radiotherapy. MATERIALS AND METHODS: The study population consisted of 120 NPC patients treated with intensity-modulated radiation therapy (IMRT). Among them 70 patients also received concurrent chemotherapy. Genotypes in DNA repair genes Ku70 c.-1310C>G (rs2267437), Ku70 c.1781G> T (rs132788), Ku80 c.2099-2408G> A (rs3835), Ku80 c.*841G> A (rs2440) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) c.2888 + 713C> T (rs2213178) were determined by polymerase chain reaction combined with the restriction fragment length polymorphism (PCR-RFLP) technique. Mucositis was scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into the CTC0-2 group (CTC toxicity grade 0, 1 and 2) and the CTC3 + group (CTC toxicity grade 3 and above). Odd ratios (OR) and 95% confidence intervals (CI) were calculated using the multivariate logistic regression analysis. RESULTS: A significant difference in Ku70 c.1781G> T genotype distribution was observed between the CTC0-2 and CTC3 + groups for the 120 patients analyzed. The GG carriers were at higher risks for severe OM (CTC3+) compared with the TT homozygotes (OR = 3.000, 95% CI = 1.287-6.994, p = 0.011). No association was found between Ku70 (c.-1310C> G), Ku80 (c.2099-2408G> A, c.*841G> A), DNA-PKcs (c.2888 + 713 C > T) and the development of severe oral mucositis. Stratification analyses for the 50 patients treated with radiation alone further confirmed the association between the variant genotype of GG and severe OM (OR = 5.128, 95% CI = 1.183-22.238, p = 0.029). Concurrent radiochemotherapy increased the risk of severe OM for both the TT homozygotes and GG genotypes. CONCLUSIONS: Our study suggests that the Ku70 c.1781G> T polymorphism may be a susceptibility factor for radiation-induced oral mucositis in Chinese nasopharyngeal carcinoma patients.

Feasibility of replacing patient specific cutouts with a computer-controlled electron multileaf collimator.

A motorized electron multileaf collimator (eMLC) was developed as an add-on device to the Varian linac for delivery of advanced electron beam therapy. It has previously been shown that electron beams collimated by an eMLC have very similar penumbra to those collimated by applicators and cutouts. Thus, manufacturing patient specific cutouts would no longer be necessary, resulting in the reduction of time taken in the cutout fabrication process. Moreover, cutout construction involves handling of toxic materials and exposure to toxic fumes that are usually generated during the process, while the eMLC will be a pollution-free device. However, undulation of the isodose lines is expected due to the finite size of the eMLC. Hence, the provided planned target volume (PTV) shape will not exactly follow the beam's-eye-view of the PTV, but instead will make a stepped approximation to the PTV shape. This may be a problem when the field edge is close to a critical structure. Therefore, in this study the capability of the eMLC to achieve the same clinical outcome as an applicator/cutout combination was investigated based on real patient computed tomographies (CTs). An in-house Monte Carlo based treatment planning system was used for dose calculation using ten patient CTs. For each patient, two plans were generated; one with electron beams collimated using the applicator/cutout combination; and the other plan with beams collimated by the eMLC. Treatment plan quality was compared for each patient based on dose distribution and dose-volume histogram. In order to determine the optimal position of the leaves, the impact of the different leaf positioning strategies was investigated. All plans with both eMLC and cutouts were generated such that 100% of the target volume receives at least 90% of the prescribed dose. Then the percentage difference in dose between both delivery techniques was calculated for all the cases. The difference in the dose received by 10% of the volume of the target was showing a mean percentage difference of 1.57%± 1.65, while the difference in the dose received by 99% of the volume was showing a mean percentage difference of 1.08%± 0.78. The mean percentage volume of Lung receiving a percentage dose equal to or greater than 20% of the prescribed dose was found to be 8.55%± 7.3 and 8.67%± 7 for the eMLC and applicator/cutout combination delivery methods respectively. Results have shown that target coverage and critical structure sparing can be effectively achieved by electron beams collimated with the eMLC. Positioning the eMLC leaves in such a way to avoids shielding any part of the projected treatment volume is most conservative and would be the recommended method to define the actual leaf position for the eMLC defined field. More optimal leaf positions can be achieved in shaping the same treatment field through the interplay of different leaf positioning strategies. We concluded that the eMLC represents an effective time saving and pollution-free device that can completely replace patient specific cutouts.

Radiosensitivity enhancement of human hepatocellular carcinoma cell line SMMC-7721 by sorafenib through the MEK/ERK signal pathway.

PURPOSE: Sorafenib, an oral multikinase inhibitor, is the first agent that has demonstrated an improved overall survival benefit in advanced hepatocellular carcinoma, setting a new standard for first-line treatment. However, the association between radiosensitivity and sorafenib remains unclear. The purpose of this study was to investigate whether sorafenib could enhance radiosensitivity and the possible mechanisms of sorafenib-mediated radiosensitization in human hepatocellular carcinoma cell line SMMC-7721. EXPERIMENTAL DESIGN: The cell viability of human hepatocellular carcinoma cell line SMMC-7721 was determined by the 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. The radiosensitization of sorafenib in SMMC-7721 cells was evaluated by clonogenic assays, and immunofluorescence for DNA double-strand break detection, and Western blotting for protein detection. RESULTS: The MTT results clearly showed that sorafenib affected cell viability in human hepatocellular cell line SMMC-7721. Sorafenib administered 1 h before the radiation treatment resulted in radiosensitization with a sensitivity enhancement ratio (SER) of 1.65 as shown by clonogenic assays. Furthermore, sorafenib pretreatment led to decreased phosphorylation levels of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) in SMMC-7721 cells. Interestingly, pretreatment of mitogen-activated protein kinase kinases/extracellular signal-regulated kinase (MEK/ERK) signaling inhibitor U0126 had a similar effect as that of sorafenib pretreatment in hepatocellular carcinoma cells, whereas pretreatment of phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling inhibitor LY294002 in the same cells had no effect on radiosensitization. The group treated with sorafenib and radiation was more sensitive to irradiation alone as demonstrated by the results of the DNA double-strand break detection. CONCLUSIONS: The combination of sorafenib and radiation affected cell viability more effectively than radiation alone. Sorafenib significantly enhanced the sensitivity of SMMC-7721 cells to radiation showing significantly reduced repair of DNA double-strand breaks. The MEK/ERK signaling pathway may be a pathway responsible for the radiosensitivity enhancement of sorafenib. Our data provided experimental support for the possible combination of sorafenib with radiation for the treatment of hepatocellular carcinoma and other cancers.

Target repositional accuracy and PTV margin verification using three-dimensional cone-beam computed tomography (CBCT) in stereotactic body radiotherapy (SBRT) of lung cancers.

The purpose of this study was to assess target repositional accuracy with respect to the bony structures using daily CBCT, and to validate the planning target volume (PTV) margin used in the lung SBRT. All patients underwent 4D CT scanning in preparation for lung SBRT. The internal target volume (ITV) was outlined from the reconstructed 4D data using the maximum-intensity projection (MIP) algorithm. A 6 mm margin was added to the ITV to create the PTV. Conformal treatment planning was performed on the helical images, to which the MIP images were fused. Prior to each treatment, CBCT was taken after a patient was set up in the treatment position. The CBCT images were fused with the simulation CT based on the bony anatomy, in order to derive setup errors and separate them from the tumor repositional errors. The treating physician then checked and modified the alignment based on target relocalization within the PTV. The shifts determined in such a method were recorded and the subtractions of these shifts with respect to the corresponding setup errors were defined as the target relocalization accuracy. Our study of 36 consecutive patients, treating 38 targets for a total of 153 fractions shows that, after setup error correction, the target repositional accuracy followed a normal distribution with the mean values close to 0 in all directions, and standard deviations of 0.25 cm in A-P, 0.24 cm in Lat, and 0.28 cm in S-I directions, respectively. The probability of having the shifts ? 0.6 cm is less than 0.8% in A-P, 0.6% in Lat, and 1.7 % in S-I directions. For the patient population studied, the target centroid position relative to the bony structures changed minimally from day to day. This demonstrated that the PTV margin that is designed on the MIP image-based ITV was adequate for lung SBRT.

On Monte Carlo modeling of megavoltage photon beams: a revisited study on the sensitivity of beam parameters.

PURPOSE: To commission Monte Carlo beam models for five Varian megavoltage photon beams (4, 6, 10, 15, and 18 MV). The goal is to closely match measured dose distributions in water for a wide range of field sizes (from 2 x 2 to 35 x 35 cm2). The second objective is to reinvestigate the sensitivity of the calculated dose distributions to variations in the primary electron beam parameters. METHODS: The GEPTS Monte Carlo code is used for photon beam simulations and dose calculations. The linear accelerator geometric models are based on (i) manufacturer specifications, (ii) corrections made by Chibani and Ma ["On the discrepancies between Monte Carlo dose calculations and measurements for the 18 MV Varian photon beam," Med. Phys. 34, 1206-1216 (2007)], and (iii) more recent drawings. Measurements were performed using pinpoint and Farmer ionization chambers, depending on the field size. Phase space calculations for small fields were performed with and without angle-based photon splitting. In addition to the three commonly used primary electron beam parameters (E(AV) is the mean energy, FWHM is the energy spectrum broadening, and R is the beam radius), the angular divergence (theta) of primary electrons is also considered. RESULTS: The calculated and measured dose distributions agreed to within 1% local difference at any depth beyond 1 cm for different energies and for field sizes varying from 2 x 2 to 35 x 35 cm2. In the penumbra regions, the distance to agreement is better than 0.5 mm, except for 15 MV (0.4-1 mm). The measured and calculated output factors agreed to within 1.2%. The 6, 10, and 18 MV beam models use theta = 0 degrees, while the 4 and 15 MV beam models require theta = 0.5 degrees and 0.6 degrees, respectively. The parameter sensitivity study shows that varying the beam parameters around the solution can lead to 5% differences with measurements for small (e.g., 2 x 2 cm2) and large (e.g., 35 x 35 cm2) fields, while a perfect agreement is maintained for the 10 x 10 cm2 field. The influence of R on the central-axis depth dose and the strong influence of theta on the lateral dose profiles are demonstrated. CONCLUSIONS: Dose distributions for very small and very large fields were proved to be more sensitive to variations in E(AV), R, and theta in comparison with the 10 x 10 cm2 field. Monte Carlo beam models need to be validated for a wide range of field sizes including small field sizes (e.g., 2 x 2 cm2).