Development of programs to predict the occurrence of mucositis from digital imaging and communications in medicine data by machine learning in head and neck volumetric modulated radiotherapy.

Volumetric modulated arc therapy (VMAT) with cisplatin for head and neck cancer is often accompanied by symptoms of pharyngeal and oral mucositis. However, no standard medical program exists for the prevention and treatment of mucositis, and the mechanisms of mucositis have not yet been fully proven. Therefore, adaptive radiotherapy (ART), which is a re-planning process, is administered when severe mucositis develops during the treatment period. We extracted the treatment plans of patients who developed severe mucositis from DICOM data and used machine learning to determine its quantitative features. This study aimed to develop a machine learning program that can predict the development of mucositis requiring ART. This study included 61 patients who received concurrent chemotherapy and radiotherapy (RT). For each patient, the equivalent square field size of each segmental irradiation field used for VMAT, dose per segment (Gy), clinical target volume high, and mean dose of the oral cavity (Gy) were calculated. Furthermore, 671 five-dimensional lists were generated from the acquired data. Support vector machine (SVM) and K-nearest neighbor (KNN) were used for machine learning. For the accuracy score, the test size was varied from 10% to 90%, and the random number of data extracted in each test size was further varied from 1 to 100 to calculate a mean accuracy score. The mean accuracy scores of SVM and KNN were 0.981 ± 0.020 and 0.972 ± 0.033, respectively. The presence or absence of ART for mucositis was classified with high accuracy. The classification of the five-dimensional list was implemented with high accuracy, and a program was constructed to predict the onset of mucositis requiring ART before treatment began. This study suggests that it may support preventive measures against mucositis and the completion of RT without having to re-plan.

Development of Machine-Learning Prediction Programs for Delivering Adaptive Radiation Therapy With Tumor Geometry and Body Shape Changes in Head and Neck Volumetric Modulated Arc Therapy.

Purpose: During radiation therapy for head and neck cancer using volumetric modulated arc therapy, excessive dosing or underdosing occurs as a result of the decrease in tumor volume and changes in body weight. Adaptive radiation therapy (ART) is performed when significant changes are observed; however, the decision to implement ART depends on the oncologist's subjective judgment. The purpose of this study was to present objective indicators for ART and develop a program to predict the need for ART. Methods and Materials: The study included 47 patients in the non-ART group and 21 patients in the ART group with shape changes. Patients who received ART could not be covered with the prescribed radiation therapy dose due to shape changes. For each patient, 1112 6-dimensional lists were created, including the number of irradiations, amount of change in the clinical target volume (CTV), rate of change in CTV, mean oral cavity dose, age, and body mass index. Support vector machine and k-nearest neighbor were used for machine learning. The random number of test data to be extracted varied from 1 to 9, and a mean accuracy score was calculated. These programs could predict the need for ART if the accuracy score was high. Results: The classification accuracy of the list, including the amount of change in the CTV and rate of change in CTV up to 20 fractions, was 0.963 and 0.967 for support vector machine and k-nearest neighbor, respectively. Conclusions: This program predicted the need for ART with more than 90% accuracy based on shape changes over time in cone beam computed tomography analysis for up to 20 fractions. This may provide significant support for objective decisions to implement ART based on the amount of change over time during treatment.

[A Preliminary Study of Optimal Imaging Acquisition Parameters for Fiducial Markers in Liver Stereotactic Body Radiotherapy].

In liver stereotactic body radiotherapy (SBRT) using fiducial markers, the accuracy of automatic image recognition of fiducial markers is important, and the imaging dose cannot be neglected in image-guided radiotherapy. Optimal imaging parameters of fiducial markers were investigated for automatic image recognition and imaging dose. We investigated automatic recognition with fiducial markers of different shapes and sizes. In addition, the optimum imaging conditions were examined based on the automatic recognition when the presence or absence of a filter, focal spot size, and phantom thickness were altered using the fiducial markers with a high automatic recognition. The results for different shapes and sizes of fiducial markers showed that larger markers were recognized more automatically, whereas shorter markers were recognized in the correct position. By using the filter, we were able to reduce the imaging dose by one third or one half compared to the case without the filter. The results for the focal spot size showed that using a larger size resulted in higher automatic recognition accuracy than using a smaller size. For the relationship between the automatically recognized imaging conditions and the air kerma when the phantom thickness was altered, it was necessary to keep the tube current-time product constant and increase the tube voltage in order to avoid poor recognition accuracy. The parameters we proposed are effective in shortening the treatment time and reducing the imaging dose because they allow us to acquire images with low doses and high accuracy of automatic recognition.

Comparison of a Hybrid IMRT/VMAT technique with non-coplanar VMAT and non-coplanar IMRT for unresectable olfactory neuroblastoma using the RayStation treatment planning system-EUD, NTCP and planning study.

The purpose of this study was to compare hybrid intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (Hybrid IMRT/VMAT), with non-coplanar (nc) IMRT and nc-VMAT treatment plans for unresectable olfactory neuroblastoma (ONB). Hybrid IMRT/VMAT, nc-IMRT and nc-VMAT plans were optimized for 12 patients with modified Kadish C stage ONB. Dose prescription was 65 Gy in 26 fractions. Dose-volume histogram parameters, conformation number (CN), homogeneity index (HI), integral dose and monitor units (MUs) delivered per fraction were assessed. Equivalent uniform dose (EUD) and normal tissue complication probability (NTCP) based on the EUD model (NTCPLogit) and the Lyman-Kutcher-Burman model (NTCPLKB) were also evaluated. We found that the Hybrid IMRT/VMAT plan significantly improved the CN for clinical target volume (CTV) and planning treatment volume (PTV) compared with the nc-VMAT plan. In general, sparing of organs at risk (OARs) is similar with the three techniques, although the Hybrid IMRT/VMAT plan resulted in a significantly reduced Dmax to contralateral (C/L) optic nerve compared with the nc-IMRT plan. The Hybrid IMRT/VMAT plan significantly reduce EUD to the ipsilateral (I/L) and C/L optic nerve in comparison with the nc-IMRT plan and nc-VMAT plan, but the difference in NTCP between the three technique was <1%. We concluded that the Hybrid IMRT/VMAT technique can offer improvement in terms of target conformity and EUD for optic nerves, while achieving equal or better OAR sparing compared with nc-IMRT and nc-VMAT, and can be a viable radiation technique for treating unresectable ONB. However, the clinical benefit of these small differences in dosimetric data, EUD and NTCP of optic nerves may be minimal.

Dose-Volume and Radiobiological Model-Based Comparative Evaluation of the Gastrointestinal Toxicity Risk of Photon and Proton Irradiation Plans in Localized Pancreatic Cancer Without Distant Metastasis.

Background: Radiobiological model-based studies of photon-modulated radiotherapy for pancreatic cancer have reported reduced gastrointestinal (GI) toxicity, although the risk is still high. The purpose of this study was to investigate the potential of 3D-passive scattering proton beam therapy (3D-PSPBT) in limiting GI organ at risk (OAR) toxicity in localized pancreatic cancer based on dosimetric data and the normal tissue complication probability (NTCP) model. Methods: The data of 24 pancreatic cancer patients were retrospectively analyzed, and these patients were planned with intensity-modulated radiotherapy (IMRT), volume-modulated arc therapy (VMAT), and 3D-PSPBT. The tumor was targeted without elective nodal coverage. All generated plans consisted of a 50.4-GyE (Gray equivalent) dose in 28 fractions with equivalent OAR constraints, and they were normalized to cover 50% of the planning treatment volume (PTV) with 100% of the prescription dose. Physical dose distributions were evaluated. GI-OAR toxicity risk for different endpoints was estimated by using published NTCP Lyman-Kutcher-Burman (LKB) models. Analysis of variance (ANOVA) was performed to compare the dosimetric data, and ΔNTCPIMRT-PSPBT and ΔNTCPVMAT-PSPBT were also computed. Results: Similar homogeneity and conformity for the clinical target volume (CTV) and PTV were exhibited by all three planning techniques (P > 0.05). 3D-PSPBT resulted in a significant dose reduction for GI-OARs in both the low-intermediate dose range (below 30 GyE) and the highest dose region (D max and V 50 GyE) in comparison with IMRT and VMAT (P < 0.05). Based on the NTCP evaluation, the NTCP reduction for GI-OARs by 3D-PSPBT was minimal in comparison with IMRT and VMAT. Conclusion: 3D-PSPBT results in minimal NTCP reduction and has less potential to substantially reduce the toxicity risk of upper GI bleeding, ulceration, obstruction, and perforation endpoints compared to IMRT and VMAT. 3D-PSPBT may have the potential to reduce acute dose-limiting toxicity in the form of nausea, vomiting, and diarrhea by reducing the GI-OAR treated volume in the low-to-intermediate dose range. However, this result needs to be further evaluated in future clinical studies.

Radiobiological model-based approach to determine the potential of dose-escalated robust intensity-modulated proton radiotherapy in reducing gastrointestinal toxicity in the treatment of locally advanced unresectable pancreatic cancer of the head.

BACKGROUND: The purpose of this study was to determine the potential of escalated dose radiation (EDR) robust intensity-modulated proton radiotherapy (ro-IMPT) in reducing GI toxicity risk in locally advanced unresectable pancreatic cancer (LAUPC) of the head in term of normal tissue complication probability (NTCP) predictive model. METHODS: For 9 patients, intensity-modulated radiotherapy (IMRT) was compared with ro-IMPT. For all plans, the prescription dose was 59.4GyE (Gray equivalent) in 33 fractions with an equivalent organ at risk (OAR) constraints. Physical dose distribution was evaluated. GI toxicity risk for different endpoints was estimated using published NTCP Lyman Kutcher Burman (LKB) models for stomach, duodenum, small bowel, and combine stomach and duodenum (Stoduo). A Wilcoxon signed-rank test was used for dosimetry parameters and NTCP values comparison. RESULT: The dosimetric results have shown that, with similar target coverage, ro-IMPT achieves a significant dose-volume reduction in the stomach, small bowel, and stoduo in low to high dose range in comparison to IMRT. NTCP evaluation for the endpoint gastric bleeding of stomach (10.55% vs. 13.97%, P = 0.007), duodenum (1.87% vs. 5.02%, P = 0.004), and stoduo (5.67% vs. 7.81%, P = 0.008) suggest reduced toxicity by ro-IMPT compared to IMRT. ∆NTCP IMRT - ro-IMPT (using parameter from Pan et al. for gastric bleed) of ≥5 to < 10% was seen in 3 patients (33%) for stomach and 2 patients (22%) for stoduo. An overall GI toxicity relative risk (NTCPro-IMPT/NTCPIMRT) reduction was noted (0.16-0.81) for all GI-OARs except for duodenum (> 1) with endpoint grade ≥ 3 GI toxicity (using parameters from Holyoake et al.). CONCLUSION: With similar target coverage and better conformity, ro-IMPT has the potential to substantially reduce the risk of GI toxicity compared to IMRT in EDR of LAUPC of the head. This result needs to be further evaluated in future clinical studies.

Frequency and predictors of detecting early locoregional recurrence/disease progression of oral squamous cell carcinoma with high-risk factors on imaging tests before postoperative adjuvant radiotherapy.

BACKGROUND: To clarify the frequency and predictors of detecting early locoregional recurrence/disease progression (LR/DP) during the interval between surgery and postoperative adjuvant radiotherapy with/without chemotherapy in patients with oral squamous cell carcinoma. METHODS: Data on 65 patients who had undergone the initial radical surgery for previously untreated oral squamous cell carcinoma which were scheduled to receive adjuvant radiotherapy with/without chemotherapy were reviewed. RESULTS: Of the 65 patients, 63 (97%) were margin-positive/close and/or extracapsular extension-positive (hereinafter, high-risk factors). Eighteen (28%) patients had abnormal findings suggestive of LR/DP on postoperative imaging. Fifteen (23%) patients were diagnosed with LR/DP and treatment policy was changed. Univariate and multivariate analyses revealed higher frequencies of abnormal findings suggestive of LR/DP (univariate/multivariate analysis, p = 0.020/0.036), diagnosing of LR/DP, and changing the treatment policy (univariate/multivariate analysis, p = 0.042/0.046), among the patients who underwent postoperative diagnostic imaging tests or radiotherapy-planning contrast-enhanced (CE) CT without diagnostic imaging tests as compared with those who underwent radiotherapy-planning non-CECT without such tests. CONCLUSION: The frequency of detecting of early LR/DP before postoperative adjuvant treatment in oral squamous cell carcinoma patients with high-risk factors was high. Furthermore, postoperative diagnostic imaging tests and radiotherapy-planning CECT may be useful to detect early LR/DP in oral squamous cell carcinoma patients before postoperative adjuvant therapy.

Patterns of failure after postoperative intensity-modulated radiotherapy for locally advanced and recurrent head and neck cancer.

OBJECTIVE: To evaluate the feasibility of postoperative intensity-modulated radiotherapy for head and neck cancer by investigating the patterns of failure after this therapy. METHODS: A retrospective chart review was performed. RESULTS: Between March 2006 and December 2013, 122 consecutive patients with head and neck squamous cell carcinoma were treated by surgery followed by postoperative intensity-modulated radiotherapy. In regard to the site of the primary tumor, 59 (48%) patients had cancer of the oral cavity, 31 (26%) patients had cancer of the hypopharynx, 14 (11%) patients had cancer of the oropharynx, 10 (8%) patients had cancer of the larynx and 8 (7%) patients had cancer of unknown primary. The median follow-up period of the surviving patients was 54 months (range, 25-115). Concurrent chemotherapy was administered in 76 patients (62%). The median prescribed radiation dose was 66 Gy. The 3-year overall survival, progression-free survival, distant metastasis free survival and loco-regional control rates were 59%, 48%, 52.4% and 71%, respectively. Of the 122 patients, 32 developed loco-regional recurrence as the initial recurrence, including in-field recurrence in 26 patients, marginal recurrence in five patients and out-field recurrence in seven patients. Of the five patients with marginal recurrence, four have had two or more surgeries before the intensity-modulated radiotherapy and three had oral cavity cancer. Severe adverse events were not frequent, occurring at a frequency of <5%, except for mucositis. No severe toxicities associated with the flap reconstruction were observed either. CONCLUSION: Postoperative intensity-modulated radiotherapy appears to be effective and feasible for patients with head and neck squamous cell carcinoma.

Evaluating positional accuracy using megavoltage cone-beam computed tomography for IMRT with head-and-neck cancer.

Accurate dose delivery is essential for the success of intensity-modulated radiation therapy (IMRT) for patients with head-and-neck (HN) cancer. Reproducibility of IMRT dose delivery to HN regions can be critically influenced by treatment-related changes in body contours. Moreover, some set-up margins may not be adaptable to positional uncertainties of HN structures at every treatment. To obtain evidence for appropriate set-up margins in various head and neck areas, we prospectively evaluated positional deviation (δ values) of four bony landmarks (i.e. the clivus and occipital protuberance for the head region, and the mental protuberance and C5 for the neck region) using megavoltage cone-beam computed tomography during a treatment course. Over 800 δ values were analyzed in each translational direction. Positional uncertainties for HN cancer patients undergoing IMRT were evaluated relative to the body mass index. Low positional accuracy was observed for the neck region compared with the head region. For the head region, most of the δ was distributed within ± 5 mm, and use of the current set-up margin was appropriate. However, the δ values for the neck region were within ± 8 mm. Especially for overweight patients, a few millimeters needed to be added to give an adequate set-up margin. For accurate dose delivery to targets and to avoid excess exposure to normal tissues, we recommend that the positional verification process be performed before every treatment.

Locoregional control after intensity-modulated radiotherapy for nasopharyngeal carcinoma with an anatomy-based target definition.

OBJECTIVE: The objective of the study was to evaluate locoregional control after intensity-modulated radiotherapy for nasopharyngeal cancer using a target definition along with anatomical boundaries. METHODS: Forty patients with biopsy-proven squamous cell or non-keratinizing carcinoma of the nasopharynx who underwent intensity-modulated radiotherapy between April 2006 and November 2009 were reviewed. There were 10 females and 30 males with a median age of 48 years (range, 17-74 years). More than half of the patients had T3/4 (n = 21) and/or N2/3 (n = 24) disease. Intensity-modulated radiotherapy was administered as 70 Gy/33 fractions with or without concomitant chemotherapy. The clinical target volume was contoured along with muscular fascia or periosteum, and the prescribed radiotherapy dose was determined for each anatomical compartment and lymph node level in the head and neck. RESULTS: One local recurrence was observed at Meckel's cave on the periphery of the high-risk clinical target volume receiving a total dose of <63 Gy. Otherwise, six locoregional failures were observed within irradiated volume receiving 70 Gy. Local and nodal control rates at 3 years were 91 and 89%, respectively. Adverse events were acceptable, and 25 (81%) of 31 patients who were alive without recurrence at 2 years had xerostomia of ≤Grade 1. The overall survival rate at 3 years was 87%. CONCLUSIONS: Target definition along with anatomically defined boundaries was feasible without compromise of the therapeutic ratio. It is worth testing this method further to minimize the unnecessary irradiated volume and to standardize the target definition in intensity-modulated radiotherapy for nasopharyngeal cancer.

Experimental evaluation of actual delivered dose using mega-voltage cone-beam CT and direct point dose measurement.

Radiation therapy in patients is planned by using computed tomography (CT) images acquired before start of the treatment course. Here, tumor shrinkage or weight loss or both, which are common during the treatment course for patients with head-and-neck (H&N) cancer, causes unexpected differences from the plan, as well as dose uncertainty with the daily positional error of patients. For accurate clinical evaluation, it is essential to identify these anatomical changes and daily positional errors, as well as consequent dosimetric changes. To evaluate the actual delivered dose, the authors proposed direct dose measurement and dose calculation with mega-voltage cone-beam CT (MVCBCT). The purpose of the present study was to experimentally evaluate dose calculation by MVCBCT. Furthermore, actual delivered dose was evaluated directly with accurate phantom setup. Because MVCBCT has CT-number variation, even when the analyzed object has a uniform density, a specific and simple CT-number correction method was developed and applied for the H&N site of a RANDO phantom. Dose distributions were calculated with the corrected MVCBCT images of a cylindrical polymethyl methacrylate phantom. Treatment processes from planning to beam delivery were performed for the H&N site of the RANDO phantom. The image-guided radiation therapy procedure was utilized for the phantom setup to improve measurement reliability. The calculated dose in the RANDO phantom was compared to the measured dose obtained by metal-oxide-semiconductor field-effect transistor detectors. In the polymethyl methacrylate phantom, the calculated and measured doses agreed within about +3%. In the RANDO phantom, the dose difference was less than +5%. The calculated dose based on simulation-CT agreed with the measured dose within±3%, even in the region with a high dose gradient. The actual delivered dose was successfully determined by dose calculation with MVCBCT, and the point dose measurement with the image-guided radiation therapy procedure.

Guidelines for respiratory motion management in radiation therapy.

Respiratory motion management (RMM) systems in external and stereotactic radiotherapies have been developed in the past two decades. Japanese medical service fee regulations introduced reimbursement for RMM from April 2012. Based on thorough discussions among the four academic societies concerned, these Guidelines have been developed to enable staff (radiation oncologists, radiological technologists, medical physicists, radiotherapy quality managers, radiation oncology nurses, and others) to apply RMM to radiation therapy for tumors subject to respiratory motion, safely and appropriately.

[Use experience and problems in the optimization of intensity modulated radiation therapy (IMRT)--Focus on head & neck].

We present the main points of the optimization in IMRT. The skin surface of the planned target volume was reduced by a few millimeters, in view of the limitations of a calculation grid in accurately estimating the influence of build-up or contamination of electrons. Air cavities such as nasal or oral cavities were, in general, filled with water equivalent density in the dose calculation. Planned target volume was contracted by 5 mm when PTV of a higher prescribed dose was delineated adjacent to it. The 5 mm width of ring-shaped ROI was set at 5 mm outside of the entire PTV to eliminate hot spots. Physical quality assurance is extremely important to eradicate unexpected dose inhomogeneity, and meticulous efforts are required.

Evaluation of the usefulness of a MOSFET detector in an anthropomorphic phantom for 6-MV photon beam.

In order to evaluate the usefulness of a metal oxide-silicon field-effect transistor (MOSFET) detector as a in vivo dosimeter, we performed in vivo dosimetry using the MOSFET detector with an anthropomorphic phantom. We used the RANDO phantom as an anthropomorphic phantom, and dose measurements were carried out in the abdominal, thoracic, and head and neck regions for simple square field sizes of 10 x 10, 5 x 5, and 3 x 3 cm(2) with a 6-MV photon beam. The dose measured by the MOSFET detector was verified by the dose calculations of the superposition (SP) algorithm in the XiO radiotherapy treatment-planning system. In most cases, the measured doses agreed with the results of the SP algorithm within +/-3%. Our results demonstrated the utility of the MOSFET detector for in vivo dosimetry even in the presence of clinical tissue inhomogeneities.

Dosimetric verification in inhomogeneous phantom geometries for the XiO radiotherapy treatment planning system with 6-MV photon beams.

We have developed a practical dose verification method for radiotherapy treatment planning systems by using only a Farmer ionization chamber in inhomogeneous phantoms. In particular, we compared experimental dose verifications of multi-layer phantom geometries and laterally inhomogeneous phantom geometries for homogeneous and inhomogenous dose calculations by using the fast-Fourier-transform convolution, fast-superposition, and superposition in the XiO radiotherapy treatment-planning system. We applied the dose verification method to three kernel-based algorithms in various phantom geometries with water-, lung- and bone-equivalent media of different field sizes. These calculations were then compared with experimental measurements by use of the Farmer ionization chamber. The fast-Fourier-transform convolution algorithm overestimated the dose by about 8% in the lung phantom geometry. The superposition algorithm and the fast-superposition algorithm were both accurate to better than 2% when compared to the measurements even for complex geometries. Our dose verification method was able to clarify the differences and equivalences of the three kernel-based algorithms and measurements with use only of commonly available apparatus. This will be generally useful in commissioning of inhomogeneity-correction algorithms in the clinical practice of treatment planning.