Clinical feasibility of a commercially available MRI-only method for radiotherapy treatment planning of the brain.

BACKGROUND: Advancements in deep-learning based synthetic computed tomography (sCT) image conversion methods have enabled the development of magnetic resonance imaging (MRI)-only based radiotherapy treatment planning (RTP) of the brain. PURPOSE: This study evaluates the clinical feasibility of a commercial, deep-learning based MRI-only RTP method with respect to dose calculation and patient positioning verification performance in RTP of the brain. METHODS: Clinical validation of dose calculation accuracy was performed by a retrospective evaluation for 25 glioma and 25 brain metastasis patients. Dosimetric and image quality of the studied MRI-only RTP method was evaluated by a direct comparison of the sCT-based and computed tomography (CT)-based external beam radiation therapy (EBRT) images and treatment plans. Patient positioning verification accuracy of sCT images was evaluated retrospectively for 10 glioma and 10 brain metastasis patients based on clinical cone-beam computed tomography (CBCT) imaging. RESULTS: An average mean dose difference of Dmean = 0.1% for planning target volume (PTV) and 0.6% for normal tissue (NT) structures were obtained for glioma patients. Respective results for brain metastasis patients were Dmean = 0.5% for PTVs and Dmean =1.0% for NTs. Global three-dimensional (3D) gamma pass rates using 2%/2 mm dose difference and distance-to-agreement (DTA) criterion were 98.0% for the glioma subgroup, and 95.2% for the brain metastasis subgroup using 1%/1 mm criterion. Mean distance differences of <1.0 mm were observed in all Cartesian directions between CT-based and sCT-based CBCT patient positioning in both subgroups. CONCLUSIONS: In terms of dose calculation and patient positioning accuracy, the studied MRI-only method demonstrated its clinical feasibility for RTP of the brain. The results encourage the use of the studied method as part of a routine clinical workflow.

Long-term outcome of biologically guided dose-escalated radiotherapy of localized prostate cancer.

BACKGROUND: Biologically created subvolumes enable non-uniform dose distributions in prostate cancer radiotherapy (RT) thus potentially improving therapeutic ratio and reducing toxicity. We present the long-term outcome of men receiving focal boosting of carbon-11 acetate (ACE) PET-CT metabolically active areas in prostate carcinoma. MATERIAL AND METHODS: Thirty men with hormone naïve localized prostate carcinoma underwent ACE PET/CT for RT planning. There were five low-, 17 intermediate-, and eight high-risk patients. Based on thresholding of the standardized uptake values (SUVs) metabolic target volumes (MTVs) corresponding to intraprostatic lesions (IPLs) were contoured. Two planning target volumes (PTVs) were applied i.e., PTVlow-risk for the whole prostate with 8-10 mm margin and PTVhigh-risk for the MTV. Pelvic nodes were not irradiated. Late toxicity of biologically guided RT was reviewed after a median of 63 months and outcome after a median follow-up of 124 months. RESULTS: Median doses to PTVlow-risk, PTVhigh-risk, prostate, and MTV were 72.9 Gy, 79.4 Gy, 76.6 Gy, and 80.4 Gy, respectively, in 38 fractions. The 10-year cancer-specific survival was 86% and the biochemical failure-free ratio 68%, respectively. The median biochemical progression-free survival (PFS) was 37, 108, and 119 months in the high, intermediate, and low-risk groups, respectively, the difference being significant between high and intermediate-risk groups (p = 0.02). One patient (3%) presented with locoregional and 5 (17%) with distant nodal metastases. Five patients (17%) had a biochemical relapse. A larger MTV was associated with shorter PFS (r = -0.41, p = 0.02), but had no influence on OS. No other statistically significant differences in the dose painting parameters were observed between recurrence-free and recurring patients. CONCLUSIONS: Biological guidance for dose-escalated prostate RT is feasible with ACE PET/CT. Since a larger MTV may be associated with a higher risk for progression, we encourage further study of dose-escalation to ACE-positive lesions considering the low toxicity of our protocol.

Repeatability of hypoxia dose painting by numbers based on EF5-PET in head and neck cancer.

BACKGROUND: Hypoxia dose painting is a radiotherapy technique to increase the dose to hypoxic regions of the tumour. Still, the clinical effect relies on the reproducibility of the hypoxic region shown in the medical image. 18F-EF5 is a hypoxia tracer for positron emission tomography (PET), and this study investigated the repeatability of 18F-EF5-based dose painting by numbers (DPBN) in head and neck cancer (HNC). MATERIALS AND METHODS: Eight HNC patients undergoing two 18F-EF5-PET/CT sessions (A and B) before radiotherapy were included. A linear conversion of PET signal intensity to radiotherapy dose prescription was employed and DPBN treatment plans were created using the image basis acquired at each PET/CT session. Also, plan A was recalculated on the image basis for session B. Voxel-by-voxel Pearson's correlation and quality factor were calculated to assess the DPBN plan quality and repeatability. RESULTS: The mean (SD) correlation coefficient between DPBN prescription and plan was 0.92 (0.02) and 0.93 (0.02) for sessions A and B, respectively, with corresponding quality factors of 0.02 (0.002) and 0.02 (0.003), respectively. The mean correlation between dose prescriptions at day A and B was 0.72 (0.13), and 0.77 (0.12) for the corresponding plans. A mean correlation of 0.80 (0.08) was found between plan A, recalculated on image basis B, and plan B. CONCLUSION: Hypoxia DPBN planning based on 18F-EF5-PET/CT showed high repeatability. This illustrates that 18F-EF5-PET provides a robust target for dose painting.

The FLUKA Monte Carlo code coupled with an OER model for biologically weighted dose calculations in proton therapy of hypoxic tumors.

INTRODUCTION: The increased radioresistance of hypoxic cells compared to well-oxygenated cells is quantified by the oxygen enhancement ratio (OER). In this study we created a FLUKA Monte Carlo based tool for inclusion of both OER and relative biological effectiveness (RBE) in biologically weighted dose (ROWD) calculations in proton therapy and applied this to explore the impact of hypoxia. METHODS: The RBE-weighted dose was adapted for hypoxia by making RBE model parameters dependent on the OER, in addition to the linear energy transfer (LET). The OER depends on the partial oxygen pressure (pO2) and LET. To demonstrate model performance, calculations were done with spread-out Bragg peaks (SOBP) in water phantoms with pO2 ranging from strongly hypoxic to normoxic (0.01-30 mmHg) and with a head and neck cancer proton plan optimized with an RBE of 1.1 and pO2 estimated voxel-by-voxel using [18F]-EF5 PET. An RBE of 1.1 and the Rørvik RBE model were used for the ROWD calculations. RESULTS: The SOBP in water had decreasing ROWD with decreasing pO2. In the plans accounting for oxygenation, the median target doses were approximately a factor 1.1 lower than the corresponding plans which did not consider the OER. Hypoxia adapted target ROWDs were considerably more heterogeneous than the RBE1.1-weighted doses. CONCLUSION: We realized a Monte Carlo based tool for calculating the ROWD. Read-in of patient pO2 and estimation of ROWD with flexibility in choice of RBE model was achieved, giving a tool that may be useful in future clinical applications of hypoxia-guided particle therapy.

Validation of automated magnetic resonance image segmentation for radiation therapy planning in prostate cancer.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) is increasingly used in radiation therapy planning of prostate cancer (PC) to reduce target volume delineation uncertainty. This study aimed to assess and validate the performance of a fully automated segmentation tool (AST) in MRI based radiation therapy planning of PC. MATERIAL AND METHODS: Pelvic structures of 65 PC patients delineated in an MRI-only workflow according to established guidelines were included in the analysis. Automatic vs manual segmentation by an experienced oncologist was compared with geometrical parameters, such as the dice similarity coefficient (DSC). Fifteen patients had a second MRI within 15 days to assess repeatability of the AST for prostate and seminal vesicles. Furthermore, we investigated whether hormonal therapy or body mass index (BMI) affected the AST results. RESULTS: The AST showed high agreement with manual segmentation expressed as DSC (mean, SD) for delineating prostate (0.84, 0.04), bladder (0.92, 0.04) and rectum (0.86, 0.04). For seminal vesicles (0.56, 0.17) and penile bulb (0.69, 0.12) the respective agreement was moderate. Performance of AST was not influenced by neoadjuvant hormonal therapy, although those on treatment had significantly smaller prostates than the hormone-naïve patients (p < 0.0001). In repeat assessment, consistency of prostate delineation resulted in mean DSC of 0.89, (SD 0.03) between the paired MRI scans for AST, while mean DSC of manual delineation was 0.82, (SD 0.05). CONCLUSION: Fully automated MRI segmentation tool showed good agreement and repeatability compared with manual segmentation and was found clinically robust in patients with PC. However, manual review and adjustment of some structures in individual cases remain important in clinical use.

Isocentric integration of intensity-modulated radiotherapy with electron fields improves field junction dose uniformity in postmastectomy radiotherapy.

BACKGROUND: In postmastectomy radiotherapy (PMRT), the dose coverage of the planning target volume (PTV) with additional margins, including the chest wall, supraclavicular, interpectoral, internal mammary and axillar level I-III lymph nodes, is often compromised. Electron fields may improve the medial dose coverage while maintaining organ at risk (OAR) doses at an acceptable level, but at the cost of hot and cold spots at the electron and photon field junction. To improve PMRT dose coverage and uniformity, an isocentric technique combining tangential intensity-modulated (IM)RT fields with one medial electron field was implemented. MATERIAL AND METHODS: For 10 postmastectomy patients isocentric IMRT with electron plans were created and compared with a standard electron/photon mix and a standard tangent technique. PTV dose uniformity was evaluated based on the tolerance range (TR), i.e. the ratio of the standard deviation to the mean dose, a dice similarity coefficient (DSC) and the 90% isodose coverage and the hot spot volumes. OAR and contralateral breast doses were also recorded. RESULTS: IMRT with electrons significantly improved the PTV dose homogeneity and conformity based on the TR and DSC values when compared with the standard electron/photon and tangent technique (p < 0.02). The 90% isodose coverage improved to 86% compared with 82% and 80% for the standard techniques (p < 0.02). Compared with the standard electron/photon mix, IMRT smoothed the dose gradient in the electron and photon field junction and the volumes receiving a dose of 110% or more were reduced by a third. For all three strategies, the OAR and contralateral breast doses were within clinically tolerable limits. CONCLUSION: Based on these results two-field IMRT combined with an electron field is a suitable strategy for PMRT.

Evaluation of adaptive radiotherapy of bladder cancer by image-based tumour control probability modelling.

UNLABELLED: Clinical implementation of adaptive radiotherapy strategies could benefit from extended tools for plan evaluation and selection. For this purpose we investigated the feasibility of image-based tumour control probability (TCP) modelling using the bladder as example of a tumour site with potential benefit from adaptive strategies. MATERIAL AND METHODS: Two bladder cancer patients that underwent planning CT and daily cone beam CT (CBCT) imaging during the treatment course were included. The bladder was outlined in every image series. Following a previously published procedure, various adaptive planning target volumes (PTVs) were generated from the inter-fractional bladder variation observed during the first four CBCT sessions. Intensity modulated treatment plans delivering 60 Gy to a given PTV were generated. In addition, simultaneous integrated boost (SIB) plans giving a 10 Gy boost to the tumour were created. Using the daily CBCT images and polynomial warping, the dose in each bladder volume element was tracked fraction by fraction. TCP calculations employing the tracked accumulated dose distributions, together with radiosensitivity parameters estimated from published data on local control of bladder cancer were performed. The dependence of TCP on the simulated clonogenic cell distribution was also explored. RESULTS: For a uniform clonogenic cell density in the whole bladder, TCP varied between 53% and 58% for the 60 Gy plans, while it was between 51% and 64% for the SIB plans. The lowest values were found when using the smallest PTVs, as they did not geometrically enclose the clinical target volume in all fractions. When increasing the clonogenic cell density in the tumour relative to that in the remaining bladder, the TCP saturated at approximately 75% for the SIB plans. CONCLUSION: Dose tracking and TCP calculation provided additional information to standard criteria such as geometrical coverage for the selected cases. TCP modelling may be a useful tool in plan evaluation and for selection between multiple plans.

A method to individualize adaptive planning target volumes for deformable targets.

We have investigated a method to individualize the planning target volume (PTV) for deformable targets in radiotherapy by combining a computer tomography (CT) scan with multiple cone beam (CB)CT scans. All combinations of the CT and up to five initial CBCTs were considered. To exclude translational motion, the clinical target volumes (CTVs) in the CBCTs were matched to the CTV in the CT. PTVs investigated were the unions, the intersections and all other structures defined by a volume with a constant CTV location frequency. The method was investigated for three bladder cancer patients with a CT and 20-27 CBCTs. Reliable alternatives to a standard PTV required use of at least four scans for planning. The CTV unions of four or five scans gave similar results when considering the fraction of individual repeat scan CTVs they volumetrically covered to at least 99%. For patient 1, 64% of the repeat scan CTVs were covered by these unions and for patient 2, 86% were covered. Further, the PTVs defined by the volume occupied by the CTV in all except one of the four or five planning scans seemed clinically feasible. On average, 52% of the repeat CBCT CTVs for patient 1 and 64% for patient 2 were covered to minimum 99% of their total volume. For patient 3, the method failed due to poor volume control of the bladder. The suggested PTVs could, with considerably improved conformity, complement the standard PTV.

The normal tissue sparing obtained with simultaneous treatment of pelvic lymph nodes and bladder using intensity-modulated radiotherapy.

BACKGROUND: We have implemented an intensity-modulated radiotherapy (IMRT) protocol for simultaneous irradiation of bladder and lymph nodes. In this report, doses to normal tissue from IMRT and our previous conformal sequential boost technique are compared. MATERIAL AND METHODS: Sixteen patients with urinary bladder cancer were treated using a six-field dynamic IMRT beam arrangement delivering 60 Gy to the bladder and 48 Gy to the pelvic lymph nodes. Dose-volume histogram (DVH) parameters for relevant normal tissues (bowel, bowel cavity, rectum and femoral heads) for the IMRT plans were compared with corresponding DVHs from our previous conformal sequential boost technique. Calculations of the generalized Equivalent Uniform Dose (gEUD) were performed for the bowel, with a reference volume of 200 cm(3) and a volume effect parameter k = 4, as well as for the rectum, using k = 12. Acute gastrointestinal (GI) and genitourinary (GU) RTOG toxicity was recorded. RESULTS: Statistical significant normal tissue sparing was obtained by IMRT. For the bowel, a significant reduction was obtained at all dose levels between 20 and 50 Gy (p < 0.05), e.g. from 180 to 121 cm(3) at 50 Gy, while the gEUD was reduced from 58 to 53 Gy (p < 0.05). Similar patterns were seen for the bowel cavity. For the rectum, IMRT reduced the maximum dose as well as the volumes receiving more than 50 and 60 Gy (p < 0.05), e.g. from 72 to 48 cm(3) at 50 Gy. The rectum gEUD was reduced from 55 to 53 Gy (p < 0.05). For the femoral heads, IMRT reduced the maximum dose as well as the volumes above all dose levels. The rate of acute peak Grade 2 GI RTOG complications was 38% after IMRT. CONCLUSION: IMRT to the urinary bladder and elective lymph nodes result in considerable normal tissue sparing compared to conformal sequential boost technique. This has paved the way for further studies combining IMRT with image-guided radiotherapy (IGRT) in bladder cancer.

The normal tissue sparing potential of adaptive strategies in radiotherapy of bladder cancer.

BACKGROUND AND PURPOSE: To improve the outcome in bladder radiotherapy by improving treatment conformation, we have investigated various adaptive treatment strategies involving on-board tumour/target visualisation for the bladder. The strategies are compared in terms of the amount of normal tissue enclosed within the PTV and the percentage volume overlap between the CTVs (i.e. bladders) on planning and repeat CT scans. MATERIALS AND METHODS: Five male bladder cancer patients having a planning and either 7 or 8 repeat scans during treatment were included in this study. Tumour positions were simulated on the sup/inf/ant/post/left/right wall and were identified in the repeat scans based on a reference coordinate system. The reference origin was positioned on an axis joining the centres of mass of the prostate and the bladder at a point mid way between the centre of mass of the bladder and the inferior bladder wall. Tumour positions on the repeat CTVs were overlapped using translation with corresponding positions on the planning CTV, after which the required isotropic and anisotropic margins were determined using a previously published margin calculation algorithm. Calculations were performed to find the margins required to enclose the envelope covering all repeat CTVs and those enclosing the repeat CTVs one by one, i.e. simulating adaptation on daily basis. These results were compared to optimising the margins for all repeat scans, firstly without any positional correction of the CTV and secondly after applying the optimum translation for the whole bladder. RESULTS: Compared with optimisation of all scans, daily adaptation increased the average percentage volume overlap by 20% to 79-82% for the various tumour positions. The volume overlap achieved was similar for no translation of the isocentre (average 79%), and slightly higher with optimal translation (average 85%). CONCLUSION: Translation of the isocentre according to tumour position did not compromise the normal tissue irradiation compared with no translation of the isocentre. Optimal translation of the isocentre is superior in terms of normal tissue sparing.

The contribution of on-line correction for rotational organ motion in image-guided radiotherapy of the bladder and prostate.

BACKGROUND AND PURPOSE: Current IGRT protocols only correct for organ motion through a 3D translational movement of the treatment couch. The aim of this study was to quantify the relative importance of rotational vs. translational corrections in bladder and prostate IGRT. MATERIALS AND METHODS: The data available consisted of a set of 9 bladder cancer patients each having a planning CT scan and between 3 and 8 repeat CT scans throughout their treatment course, with the bladder and prostate (for 5 of the 6 male patients) outlined on all scans. An algorithm was written to determine both the optimum translation and rotation angles required to align the repeat CTVs with their planning CTV. Angles considered were those possible through couch roll, rotation and tilt. The optimum shifts and angles were determined as those that minimised the volume of the repeat scan CTV lying outside the volume of the planning CTV. Two different situations were investigated: 1) 3D translation only (3 degrees of freedom (DoF)) and 2) rotation after applying the optimum 3D translation (6 DoF). Those repeat scans where rotation provided the greatest increase in CTV coverage were further investigated by determining the effect of rotation on the size of the treatment margins required and the volume of the resulting PTV. RESULTS: For the bladder, the overall average volume percentage (across scans and patients) of the repeat CTV included in the planning scan CTV was increased from 85.7% without IGRT to 89.5 and 90.1% with 3 DoF and 6 DoF, respectively. The corresponding results for the prostate were 79.4, 86.9 and 87.5%. The resulting decrease in treatment margins required was determined for the 3 bladder and 3 prostate situations where including rotation had the largest impact. In 2 of the 6 situations the resulting PTV volume was reduced by approximately 20% when using an isotropic margin, but this reduction was considerably less when the margins were individually optimised. CONCLUSION: When treating either the bladder or prostate alone, translational IGRT correction was by far the most important action necessary to ensure alignment of the repeat CTV with the planning CTV.