Summary Radiotherapy has long been the mainstay of treatment for patients with head and neck cancer and has traditionally involved a stage-dependent strategy whereby all patients with the same TNM ...stage receive the same therapy. We believe there is a substantial opportunity to improve radiotherapy delivery beyond just technological and anatomical precision. In this Series paper, we explore several new ideas that could improve understanding of the phenotypic and genotypic differences that exist between patients and their tumours. We discuss how exploiting these differences and taking advantage of precision medicine tools—such as genomics, radiomics, and mathematical modelling—could open new doors to personalised radiotherapy adaptation and treatment. We propose a new treatment shift that moves away from an era of empirical dosing and fractionation to an era focused on the development of evidence to guide personalisation and biological adaptation of radiotherapy. We believe these approaches offer the potential to improve outcomes and reduce toxicity.
Purpose
Despite improvements in optimization and automation algorithms, the quality of radiation treatment plans still varies dramatically. A tool that allows a priori estimation of the best possible ...sparing (Feasibility DVH, or FDVH) of an organ at risk (OAR) in high‐energy photon planning may help reduce plan quality variability by deriving patient‐specific OAR goals prior to optimization. Such a tool may be useful for (a) meaningfully evaluating patient‐specific plan quality and (b) supplying best theoretically achievable DVH goals, thus pushing the solution toward automatic Pareto optimality. This work introduces such a tool and validates it for clinical Head and Neck (HN) datasets.
Methods
To compute FDVH, first the targets are assigned uniform prescription doses, with no reference to any particular beam arrangement. A benchmark 3D dose built outside the targets is estimated using a series of energy‐specific dose spread calculations reflecting observed properties of radiation distribution in media. For the patient, the calculation is performed on the heterogeneous dataset, taking into account the high‐ (penumbra driven) and low‐ (PDD and scatter‐driven) gradient dose spreading. The former is driven mostly by target dose and surface shape, while the latter adds the dependence on target volume. This benchmark dose is used to produce the “best possible sparing” FDVH for an OAR, and based on it, progressively more easily achievable FDVH curves can be estimated. Validation was performed using test cylindrical geometries as well as 10 clinical HN datasets. For HN, VMAT plans were prepared with objectives of covering the primary and the secondary (bilateral elective neck) PTVs while addressing only one OAR at a time, with the goal of maximum sparing. The OARs were each parotid, the larynx, and the inferior pharyngeal constrictor. The difference in mean OAR doses was computed for the achieved vs. FDVHs, and the shapes of those DVHs were compared by means of the Dice similarity coefficient (DSC).
Results
For all individually optimized HN OARs (N = 38), the average DSC between the planned DVHs and the FDVHs was 0.961 ± 0.018 (95% CI 0.955–0.967), with the corresponding average of mean OAR dose differences of 1.8 ± 5.8% (CI −0.1–3.6%). For realistic plans the achieved DVHs run no lower than the FDVHs, except when target coverage is compromised at the target/OAR interface.
Conclusions
For the validation of VMAT plans, the OAR DVHs optimized one‐at‐a‐time were similar in shape to and bound on the low side by the FDVHs, within the confines of planner's ability to precisely cover the target(s) with the prescription dose(s). The method is best suited for the OARs close to the target. This approach is fundamentally different from “knowledge‐based planning” because it is (a) independent of the treatment plan and prior experience, and (b) it approximates, from nearly first principles, the lowest possible boundary of the OAR DVH, but not necessarily its actual shape in the presence of competing OAR sparing and target dose homogeneity objectives.
. To reduce the magnetic isocenter position variation with gantry rotation on an 0.35 T MRI-guided linac to a practically negligible level.
. Central fRequency (CF) offset, eddy current calibration, ...cross-term calibration, gradient delay, and gradient offsets are tuned for each MR linac installation at every 30° of gantry rotation and stored in a look-up table (LUT). During treatment, the CF is tuned only once in the beginning at an arbitrary gantry angle. After that, imaging paramters are offset based on the stored LUT values for any given gantry angle.
. For the same hardware configuration, the implementation of the gantry-angle-specific parameter corrections reduced the total isocenters range of travel in the transverse plane from 1.1 to 0.3 mm and from 0.8 to 0.2 mm in horizontal and vertical directions, respectively. With the longitudinal shift always being negligible (≤0.2 mm), the radius of the sphere encompassing the isocenter locations was reduced from 0.6 to 0.2 mm. Geometric distortion improved as well; in particular, the gantry-angle-averaged maximum longitudinal distortion within a 35 cm diameter sphere was reduced from 1.4 to 0.8 mm. Since the CF is tuned only once during treatment, imaging may resume promptly after the gantry reaches the next target position.
. The MRI-guided linear accelerator was conceived primarily as an instrument for precision image-guided therapy. Thus, it is important to keep the treatment and imaging isocentres as close as possible while minimizing the geometric distortion. The described solution reduces the walkout of the imaging isocenter to a fraction of 1 mm, while keeping geometric distortion in a substantial volume below 1 mm. The approach is robust and does not increase the overall procedure time.
A high‐resolution diode array has been comprehensively evaluated. It consists of 1013 point diode detectors arranged on the two 7.7 × 7.7 cm2 printed circuit boards (PCBs). The PCBs are aligned face ...to face in such a way that the active volumes of all diodes are in the same plane. All individual correction factors required for accurate dosimetry have been validated for conventional and flattening filter free (FFF) 6MV beams. That included diode response equalization, linearity, repetition rate dependence, field size dependence, angular dependence at the central axis and off‐axis in the transverse, sagittal, and multiple arbitrary planes. In the end‐to‐end tests the array and radiochromic film dose distributions for SRS‐type multiple‐target plans were compared. In the equalization test (180° rotation), the average percent dose error between the normal and rotated positions for all diodes was 0.01% ± 0.1% (range −0.3 to 0.4%) and −0.01% ± 0.2% (range −0.9 to 0.9%) for 6 MV and 6MV FFF beams, respectively. For the axial angular response, corrected dose stayed within 2% from the ion chamber for all gantry angles, until the beam direction approached the detector plane. In azimuthal direction, the device agreed with the scintillator within 1% for both energies. For multiple combinations of couch and gantry angles, the average percent errors were −0.00% ± 0.6% (range: −2.1% to 1.6%) and −0.1% ± 0.5% (range −1.6% to 2.1%) for the 6MV and 6MV FFF beams, respectively. The measured output factors were largely within 2% of the scintillator, except for the 5 mm 6MV beam showing a 3.2% deviation. The 2%/1 mm gamma analysis of composite SRS measurements produced the 97.2 ± 1.3% (range 95.8‐98.5%) average passing rate against film. Submillimeter (≤0.5 mm) dose profile alignment with film was demonstrated in all cases.
Stereotactic body radiation therapy (SBRT) has emerged as a viable reirradiation strategy for locally recurrent previously-irradiated head and neck cancer. Doses in the literature have varied, which ...challenges clinical application of SBRT as well as clinical trial design.
A working group was formed through the American Association of Physicists in Medicine to study tumor control probabilities for SBRT in head and neck cancer. We herein present a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally recurrent previously-irradiated head and neck cancer. Dose-response models are generated that present tumor control probability as a function of dose.
Data from more than 300 cases in 8 publications suggest that there is a dose-response relationship, with superior local control and possibly improved overall survival for doses of 35 to 45 Gy (in 5 fractions) compared with <30 Gy.
Stereotactic body radiation therapy doses equivalent to 5-fraction doses of 40 to 50 Gy are suggested for retreatment.
MRI is often used in tumor localization for radiotherapy treatment planning, with gadolinium (Gd)-containing materials often introduced as a contrast agent. Motexafin gadolinium is a novel ...radiosensitizer currently being studied in clinical trials. The nanoparticle technologies can target tumors with high concentration of high-Z materials. This Monte Carlo study is the first detailed quantitative investigation of high-Z material Gd-induced dose enhancement in megavoltage external beam photon therapy. BEAMnrc, a radiotherapy Monte Carlo simulation package, was used to calculate dose enhancement as a function of Gd concentration. Published phase space files for the TrueBeam flattening filter free (FFF) and conventional flattened 6MV photon beams were used. High dose rate (HDR) brachytherapy with Ir-192 source was also investigated as a reference. The energy spectra difference caused a dose enhancement difference between the two beams. Since the Ir-192 photons have lower energy yet, the photoelectric effect in the presence of Gd leads to even higher dose enhancement in HDR. At depth of 1.8 cm, the percent mean dose enhancement for the FFF beam was 0.38±0.12, 1.39±0.21, 2.51±0.34, 3.59±0.26, and 4.59±0.34 for Gd concentrations of 1, 5, 10, 15, and 20 mg/mL, respectively. The corresponding values for the flattened beam were 0.09±0.14, 0.50±0.28, 1.19±0.29, 1.68±0.39, and 2.34±0.24. For Ir-192 with direct contact, the enhanced were 0.50±0.14, 2.79±0.17, 5.49±0.12, 8.19±0.14, and 10.80±0.13. Gd-containing materials used in MRI as contrast agents can also potentially serve as radiosensitizers in radiotherapy. This study demonstrates that Gd can be used to enhance radiation dose in target volumes not only in HDR brachytherapy, but also in 6 MV FFF external beam radiotherapy, but higher than the currently used clinical concentration (>5 mg/mL) would be needed.
Pencil beam (PB) and collapsed cone convolution (CCC) dose calculation algorithms differ significantly when used in the thorax. However, such differences have seldom been previously directly ...correlated with outcomes of lung stereotactic ablative body radiation (SABR).
Data for 201 non-small cell lung cancer patients treated with SABR were analyzed retrospectively. All patients were treated with 50 Gy in 5 fractions of 10 Gy each. The radiation prescription mandated that 95% of the planning target volume (PTV) receive the prescribed dose. One hundred sixteen patients were planned with BrainLab treatment planning software (TPS) with the PB algorithm and treated on a Novalis unit. The other 85 were planned on the Pinnacle TPS with the CCC algorithm and treated on a Varian linac. Treatment planning objectives were numerically identical for both groups. The median follow-up times were 24 and 17 months for the PB and CCC groups, respectively. The primary endpoint was local/marginal control of the irradiated lesion. Gray's competing risk method was used to determine the statistical differences in local/marginal control rates between the PB and CCC groups.
Twenty-five patients planned with PB and 4 patients planned with the CCC algorithms to the same nominal doses experienced local recurrence. There was a statistically significant difference in recurrence rates between the PB and CCC groups (hazard ratio 3.4 95% confidence interval: 1.18-9.83, Gray's test P=.019). The differences (Δ) between the 2 algorithms for target coverage were as follows: ΔD99GITV = 7.4 Gy, ΔD99PTV = 10.4 Gy, ΔV90GITV = 13.7%, ΔV90PTV = 37.6%, ΔD95PTV = 9.8 Gy, and ΔDISO = 3.4 Gy. GITV = gross internal tumor volume.
Local control in patients receiving who were planned to the same nominal dose with PB and CCC algorithms were statistically significantly different. Possible alternative explanations are described in the report, although they are not thought likely to explain the difference. We conclude that the difference is due to relative dosimetric underdosing of tumors with the PB algorithm.
It remains unclear how localized radiotherapy for cancer metastases can occasionally elicit a systemic antitumor effect, known as the abscopal effect, but historically, it has been speculated to ...reflect the generation of a host immunotherapeutic response. The ability to purposefully and reliably induce abscopal effects in metastatic tumors could meet many unmet clinical needs. Here, we describe a mathematical model that incorporates physiologic information about T-cell trafficking to estimate the distribution of focal therapy-activated T cells between metastatic lesions. We integrated a dynamic model of tumor-immune interactions with systemic T-cell trafficking patterns to simulate the development of metastases. In virtual case studies, we found that the dissemination of activated T cells among multiple metastatic sites is complex and not intuitively predictable. Furthermore, we show that not all metastatic sites participate in systemic immune surveillance equally, and therefore the success in triggering the abscopal effect depends, at least in part, on which metastatic site is selected for localized therapy. Moreover, simulations revealed that seeding new metastatic sites may accelerate the growth of the primary tumor, because T-cell responses are partially diverted to the developing metastases, but the removal of the primary tumor can also favor the rapid growth of preexisting metastatic lesions. Collectively, our work provides the framework to prospectively identify anatomically defined focal therapy targets that are most likely to trigger an immune-mediated abscopal response and therefore may inform personalized treatment strategies in patients with metastatic disease.
Predicting recurrence after stereotactic body radiotherapy (SBRT) in non-small cell lung cancer (NSCLC) patients is problematic, but critical for the decision of following treatment. This study aims ...to investigate the association of imaging features derived from the first follow-up computed tomography (CT) on lung cancer patient outcomes following SBRT, and identify patients at high risk of recurrence.
Fifty nine biopsy-proven non-small cell lung cancer patients were qualified for this study. The first follow-up CTs were performed about 3 months after SBRT (median time: 91 days). Imaging features included 34 manually scored radiological features (semantics) describing the lesion, lung and thorax and 219 quantitative imaging features (radiomics) extracted automatically after delineation of the lesion. Cox proportional hazard models and Harrel's C-index were used to explore predictors of overall survival (OS), recurrence-free survival (RFS), and loco-regional recurrence-free survival (LR-RFS). Five-fold cross validation was performed on the final prognostic model.
The median follow-up time was 42 months. The model for OS contained Eastern Cooperative Oncology Group (ECOG) performance status (HR = 3.13, 95% CI: 1.17-8.41), vascular involvement (HR = 3.21, 95% CI: 1.29-8.03), lymphadenopathy (HR = 3.59, 95% CI: 1.58-8.16) and the 1st principle component of radiomic features (HR = 1.24, 95% CI: 1.02-1.51). The model for RFS contained vascular involvement (HR = 3.06, 95% CI: 1.40-6.70), vessel attachment (HR = 3.46, 95% CI: 1.65-7.25), pleural retraction (HR = 3.24, 95% CI: 1.41-7.42), lymphadenopathy (HR = 6.41, 95% CI: 2.58-15.90) and relative enhancement (HR = 1.40, 95% CI: 1.00-1.96). The model for LR-RFS contained vascular involvement (HR = 4.96, 95% CI: 2.23-11.03), lymphadenopathy (HR = 2.64, 95% CI: 1.19-5.82), circularity (F13, HR = 1.60, 95% CI: 1.10-2.32) and 3D Laws feature (F92, HR = 1.96, 95% CI: 1.35-2.83). Five-fold cross-validated the areas under the receiver operating characteristic curves (AUC) of these three models were all above 0.8.
Our analysis reveals disease progression could be prognosticated as early as 3 months after SBRT using CT imaging features, and these features would be helpful in clinical decision-making.
Abstract Radiomics is being explored for potential applications in radiation therapy. How various imaging protocols affect quantitative image features is currently a highly active area of research. ...To assess the variability of image features derived from conventional three-dimensional (3D) and respiratory-gated (RG) positron emission tomography (PET)/computed tomography (CT) images of lung cancer patients, image features were computed from 23 lung cancer patients. Both protocols for each patient were acquired during the same imaging session. PET tumor volumes were segmented using an adaptive technique which accounted for background. CT tumor volumes were delineated with a commercial segmentation tool. Using RG PET images, the tumor center of mass motion, length, and rotation were calculated. Fifty-six image features were extracted from all images consisting of shape descriptors, first-order features, and second-order texture features. Overall, 26.6% and 26.2% of total features demonstrated less than 5% difference between 3D and RG protocols for CT and PET, respectively. Between 10 RG phases in PET, 53.4% of features demonstrated percent differences less than 5%. The features with least variability for PET were sphericity, spherical disproportion, entropy (first and second order), sum entropy, information measure of correlation 2, Short Run Emphasis (SRE), Long Run Emphasis (LRE), and Run Percentage (RPC); and those for CT were minimum intensity, mean intensity, Root Mean Square (RMS), Short Run Emphasis (SRE), and RPC. Quantitative analysis using a 3D acquisition versus RG acquisition (to reduce the effects of motion) provided notably different image feature values. This study suggests that the variability between 3D and RG features is mainly due to the impact of respiratory motion.
PDF
