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Purpose: Radiation therapy techniques have developed from 3-dimensional conformal radiation therapy (3DCRT) to intensity modulated radiation therapy (IMRT), with better sparing of the surrounding normal tissues. The current analysis aimed to investigate whether IMRT, compared to 3DCRT, resulted in fewer adverse events (AEs) and patient-reported symptoms in the randomized PORTEC-3 trial for high-risk endometrial cancer.Methods and materials: Data on AEs and patient-reported quality of life (QoL) of the PORTEC-3 trial were available for analysis. Physician-reported AEs were graded using Common Terminology Criteria for Adverse Events v3.0. QoL was assessed by the European Organisation for Research and Treatment of Cancer QLQC30, CX24, and OV28 questionnaires. Data were compared between 3DCRT and IMRT. A P value of = .01 was considered statistically significant due to the risk of multiple testing. For QoL, combined scores 1 to 2 ("not at all" and "a little") versus 3 to 4 ("quite a bit" and "very much") were compared between the techniques.Results: Of 658 evaluable patients, 559 received 3DCRT and 99 IMRT. Median follow-up was 74.6 months. During treatment no significant differences were observed, with a trend for more grade =3 AEs, mostly hematologic and gastrointestinal, after 3DCRT (37.7% vs 26.3%, P = .03). During follow-up, 15.4% (vs 4%) had grade >= 2 diarrhea, and 26.1% (vs 13.1%) had grade >= 2 hematologic AEs after 3DCRT (vs IMRT) (both P < .01). Among 574 (87%) patients evaluable for QoL, 494 received 3DCRT and 80 IMRT. During treatment, 37.5% (vs 28.6%) reported diarrhea after 3DCRT (vs IMRT) (P = .125); 22.1% (versus 10.0%) bowel urgency (P = 0039), and 18.2% and 8.6% abdominal cramps (P = .058). Other QoL scores showed no differences.Conclusions: IMRT resulted in fewer grade >= 3 AEs during treatment and significantly lower rates of grade >= 2 diarrhea and hematologic AEs during follow-up. Trends toward fewer patient-reported bowel urgency and abdominal cramps were observed after IMRT compared to 3DCRT. (C) 2021 The Authors. Published by Elsevier Inc.

Highlights • Eye and tumour deformation due to gravity is less than 0.4 mm. • Conformity index between flexed and supine position for eyes is >0.95. • Conformity index between flexed and supine position for tumours is >0.85. • Supinely acquired MR images can be used for PBT planning., Proton beam therapy (PBT) for uveal melanoma (UM) is performed in sitting position, while the acquisition of the Magnetic resonance (MR)-images for treatment planning is performed in supine position. We assessed the effect of this difference in position on the eye- and tumour- shape. Seven subjects and six UM-patients were scanned in supine and a seating mimicking position. The distances between the tumour/sclera in both positions were calculated. The median distance between both positions was 0.1 mm. Change in gravity direction produced no substantial changes in sclera and tumour shape, indicating that supinely acquired MR-images can be used to plan ocular-PBT.

Highlights • Issues of MRI that are relevant for radiation oncologists are addressed. • Radiation oncology requires dedicated scan protocols. • Use of diagnostic protocols is not recommended for radiotherapy. • MR images must be made in treatment position with the standard positioning devices. • Safety screening prior to entering the MRI room is crucial., MRI is increasingly used in radiation oncology to facilitate tumor and organ-at-risk delineation and image guidance. In this review, we address issues of MRI that are relevant for radiation oncologists when interpreting MR images offered for radiotherapy. Whether MRI is used in combination with CT or in an MRI-only workflow, it is generally necessary to ensure that MR images are acquired in treatment position, using the positioning and fixation devices that are commonly applied in radiotherapy. For target delineation, often a series of separate image sets are used with distinct image contrasts, acquired within a single exam. MR images can suffer from image distortions. While this can be avoided with dedicated scan protocols, in a diagnostic setting geometrical fidelity is less relevant and is therefore less accounted for. Since geometrical fidelity is of utmost importance in radiation oncology, it requires dedicated scan protocols. The strong magnetic field of an MRI scanner and the use of radiofrequency radiation can cause safety hazards if not properly addressed. Safety screening is crucial for every patient and every operator prior to entering the MRI room.

Background: Intensity-modulated proton therapy is sensitive to inter-fraction variations, including density changes along the pencil-beam paths and variations in organ-shape and location. Large day-to-day variations are seen for cervical cancer patients. The purpose of this study was to develop and evaluate a novel method for online selection of a plan from a patient-specific library of prior plans for different anatomies, and adapt it for the daily anatomy. Material and methods: The patient-specific library of prior plans accounting for altered target geometries was generated using a pretreatment established target motion model. Each fraction, the best fitting prior plan was selected. This prior plan was adapted using (1) a restoration of spot-positions (Bragg peaks) by adapting the energies to the new water equivalent path lengths; and (2) a spot addition to fully cover the target of the day, followed by a fast optimization of the spot-weights with the reference point method (RPM) to obtain a Pareto-optimal plan for the daily anatomy. Spot addition and spot-weight optimization could be repeated iteratively. The patient cohort consisted of six patients with in total 23 repeat-CT scans, with a prescribed dose of 45 Gy(RBE) to the primary tumor and the nodal CTV. Using a 1-plan-library (one prior plan based on all motion in the motion model) was compared to choosing from a 2-plan-library (two prior plans based on part of the motion). Results: Applying the prior-plan adaptation method with one iteration of adding spots resulted in clinically acceptable target coverage (V95%≥95% and V107%≤2%) for 37/46 plans using the 1-plan-library and 41/46 plans for the 2-plan-library. When adding spots twice, the 2-plan-library approach could obtain acceptable coverage for all scans, while the 1-plan-library approach showed V107%>2% for 3/46 plans. Similar OAR results were obtained. Conclusion: The automated prior-plan adaptation method can successfully adapt for the large day-to-day variations observed in cervical cancer patients.

Background and purpose The impact of treatment accuracy on NTCP-based patient selection for proton therapy is currently unknown. This study investigates this impact for oropharyngeal cancer patients. Materials and methods Data of 78 patients was used to automatically generate treatment plans for a simultaneously integrated boost prescribing 70 Gy RBE /54.25 Gy RBE in 35 fractions. IMRT treatment plans were generated with three different margins; intensity modulated proton therapy (IMPT) plans for five different setup and range robustness settings. Four NTCP models were evaluated. Patients were selected for proton therapy if NTCP reduction was ≥10% or ≥5% for grade II or III complications, respectively. Results The degree of robustness had little impact on patient selection for tube feeding dependence, while the margin had. For other complications the impact of the robustness setting was noticeably higher. For high-precision IMRT (3 mm margin) and high-precision IMPT (3 mm setup/3% range error), most patients were selected for proton therapy based on problems swallowing solid food (51.3%) followed by tube feeding dependence (37.2%), decreased parotid flow (29.5%), and patient-rated xerostomia (7.7%). Conclusions Treatment accuracy has a significant impact on the number of patients selected for proton therapy. Therefore, it cannot be ignored in estimating the number of patients for proton therapy.

As the benefits, limitations and contraindications of transoral laser microsurgery (TLM) in glottic carcinoma treatments become better defined, pre-treatment imaging has become more important to assess the case-specific suitability of TLM and to predict functional outcomes both for treatment consideration and patient counseling. Magnetic resonance imaging (MRI) is the preferred modality to image such laryngeal tumors, even though imaging the larynx using MRI can be difficult. The first challenge is that there are no commercial radiofrequency (RF) coils that are specifically designed for imaging the larynx, and performance in terms of coverage and signal-to-noise ratio (SNR) is compromised using general-purpose RF coils. Secondly, motion in the neck region induced by breathing, swallowing and vessel pulsation can induce severe image artefacts, sometimes rendering the images unusable. In this paper we design a dedicated RF coil array which allows high quality high resolution imaging of the larynx. In addition we show that introducing respiratory-triggered acquisition improves the diagnostic quality of the images by minimizing breathing and swallowing artefacts. Together, these developments enable robust, essentially artefact-free images of the full larynx with an isotropic resolution of 1 mm to be acquired within a few minutes.

Background: Proton therapy is becoming increasingly available, so it is important to apply objective and individualized patient selection to identify those who are expected to benefit most from proton therapy compared to conventional intensity modulated radiation therapy (IMRT). Comparative treatment planning using normal tissue complication probability (NTCP) evaluation has recently been proposed. This work investigates the impact of NTCP model and dose uncertainties on model-based patient selection. Material and Methods: We used IMRT and intensity modulated proton therapy (IMPT) treatment plans of 78 oropharyngeal cancer patients, which were generated based on automated treatment planning and evaluated based on three published NTCP models. A reduction in NTCP of more than a certain threshold (e.g. 10% lower NTCP) leads to patient selection for IMPT, referred to as ‘nominal’ selection. To simulate the effect of uncertainties in NTCP-model coefficients (based on reported confidence intervals) and planned doses on the accuracy of model-based patient selection, the Monte Carlo method was used to sample NTCP-model coefficients and doses from a probability distribution centered at their nominal values. Patient selection accuracy within a certain sample was defined as the fraction of patients which had similar selection in both the ‘nominal’ and ‘sampled’ scenario. Results: For all three NTCP models, the median patient selection accuracy was found to be above 70% when only NTCP-model uncertainty was considered. Selection accuracy decreased with increasing uncertainty resulting from differences between planned and delivered dose. In case of excessive dose uncertainty, selection accuracy decreased to 60%. Conclusion: Model and dose uncertainty highly influence the accuracy of model-based patient selection for proton therapy. A reduction of NTCP-model uncertainty is necessary to reach more accurate model-based patient selection.

Purpose. To investigate the robustness of single vocal cord intensity modulated radiation therapy (IMRT) treatment plans for set-up errors, respiration, and deformation. Material and methods. Four-dimensional computed tomography (4D-CT) scans of 10 early glottic carcinoma patients, previously treated with conventional techniques, were used in this simulation study. For each patient a pre-treatment 4D-CT was used for IMRT planning, generating a reference dose distribution. Prescribed PTV dose was 66 Gy. The impact of systematic set-up errors was simulated by applying shifts of ± 2 mm to the planning CT scans, followed by dose re-calculation with original beam segments, MUs, etc. Effects of respiration and deformation were determined utilizing extreme inhale and exhale CT scans, and repeat scans acquired after 22 Gy, 44 Gy, and 66 Gy, respectively. All doses were calculated using Monte Carlo dose simulations. Results. Considering all investigated geometrical perturbations, reductions in the clinical target volume (CTV) V95%, D98%, D2%, and generalized equivalent uniform dose (gEUD) were limited to 1.2 ± 2.2%, 2.4 ± 2.9%, 0.2 ± 1.8%, and 0.6 ± 1.1 Gy, respectively. The near minimum dose, D98%, was always higher than 89%, and gEUD always remained higher than 66 Gy. Planned contra-lateral (CL) vocal cord DMean, gEUD, and V40 Gy were 38.2 ± 6.0 Gy, 43.4 ± 5.6 Gy, and 42.7 ± 14.9%. With perturbations these values changed by −0.1 ± 4.3 Gy, 0.1 ± 4.0 Gy, and −1.0 ± 9.6%, respectively. Conclusions. On average, CTV dose reductions due to geometrical perturbations were very low, and sparing of the CL vocal cord was maintained. In a few observations (6 of 103 simulated situations), the near-minimum CTV-dose was around 90%, requiring attention in deciding on a future clinical protocol.

Purpose: To investigate interfraction setup variations of the primary tumor, elective nodes, and vertebrae in laryngeal cancer patients and to validate protocols for cone beam computed tomography (CBCT)-guided correction.Methods and Materials: For 30 patients, CBCT-measured displacements in fractionated treatments were used to investigate population setup errors and to simulate residual setup errors for the no action level (NAL) offline protocol, the extended NAL (eNAL) protocol, and daily CBCT acquisition with online analysis and repositioning.Results: Without corrections, 12 of 26 patients treated with radical radiation therapy would have experienced a gradual change (time trend) in primary tumor setup >= 4 mm in the cranio-caudal (CC) direction during the fractionated treatment (11/12 in caudal direction, maximum 11 mm). Due to these trends, correction of primary tumor displacements with NAL resulted in large residual CC errors (required margin 6.7 mm). With the weekly correction vector adjustments in eNAL, the trends could be largely compensated (CC margin 3.5 mm). Correlation between movements of the primary and nodal clinical target volumes (CTVs) in the CC direction was poor (r(2) = 0.15). Therefore, even with online setup corrections of the primary CTV, the required CC margin for the nodal CTV was as large as 6.8 mm. Also for the vertebrae, large time trends were observed for some patients. Because of poor CC correlation (r(2) = 0.19) between displacements of the primary CTV and the vertebrae, even with daily online repositioning of the vertebrae, the required CC margin around the primary CTV was 6.9 mm.Conclusions: Laryngeal cancer patients showed substantial interfraction setup variations, including large time trends, and poor CC correlation between primary tumor displacements and motion of the nodes and vertebrae (internal tumor motion). These trends and nonrigid anatomy variations have to be considered in the choice of setup verification protocol and planning target volume margins. eNAL could largely compensate time trends with minor prolongation of fraction time. (c) 2013 Elsevier Inc.

Introduction: The treatment of choice for early glottic cancer is still being debated; ultimately it relies on the functional outcome. This paper reports on a novel sparing 4D conformal technique for single vocal cord irradiation (SVCI). Material and methods: The records of 164 T1a patients with SCC of the vocal cord, irradiated in the Erasmus MC between 2000 and 2008, were analyzed for local control and overall survival. The quality of life was determined by EORTC H&N35 questionnaires. Also the VHI (voice handicap index), and the TSH (thyroid stimulating hormone) blood levels, were established. On-line image guided SVCI, using cone beam CT or stereotactic radiation therapy (SRT) techniques, were developed. Results: A LC rate at five-years of 93% and a VHI of 12.7 (0-63) was determined. It appeared feasible to irradiate one vocal cord within 1-2 mm accuracy. This way sparing of the contralateral (CL) vocal cord and CL normal tissues, could be achieved. Conclusions: Given the accuracy (1-2 mm) and small volume disease (CTV limited to one vocal cord), for the use of stereotactic RT techniques SVCI with large fraction sizes is currently being investigated in clinic. It is argued that hypofractionated SVCI can be a competitive alternative to laser surgery. (C) 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 101 (2011) 415-419

Purpose: To evaluate whether magnetic-resonance (MR) sialography can be used to investigate radiationinduced xerostomia. Preradiotherapy (pre-RT) and postradiotherapy (post-RT) MR sialographic images of the major salivary ducts (parotid and submandibular) were compared. Methods and Materials: Magnetic-resonance sialography was performed pre-RT, and 6 weeks and 6 months post-RT on 9 patients with T1-4N0-2M0 naso- or oropharyngeal tumors, on a 1.5-T MR scanner. Patients were positioned in the scanner, using a radiotherapy immobilization mask. Image registration of the MR sialograms pre- and post-RT with each other and with the CT and consequently the dose distribution was performed. A categorical scoring system was used to compare the visibility of ducts pre-RT and post-RT. Results: Good-quality MR sialographic images were obtained, and image registration was successful in all cases. The visibility score of the parotid ducts and submandibular ducts was reduced at 6 weeks post-RT, which means that the full trajectory of the salivary ducts, from the intraglandular space to the mouth cavity, was only partially visualized. For some of the parotid ducts, the visibility score improved at 6 months post-RT, but not for the submandibular ducts. The mean dose for the parotid glands was 35 Gy (1 standard deviation [SD] 3 Gy), and for the submandibular glands it was 62 Gy (SD, 8 Gy). Conclusion: Three-dimensional MR sialography is a promising approach for investigating xerostomia, because radiation-induced changes to the saliva content of the ducts can be visualized. © 2007 Elsevier Inc. 3D MR sialography, Xerostomia, Salivary glands, IMRT, Head-and-neck radiotherapy.

PURPOSE: To investigate the effect of random setup uncertainties on the highly conformal dose distributions produced by intensity-modulated radiotherapy (IMRT) for clinical head-and-neck cancer patients and to determine adequate margins to account for those uncertainties. METHODS AND MATERIALS: We have implemented in our clinical treatment planning system the possibility of simulating normally distributed patient setup displacements, translations, and rotations. The planning CT data of 8 patients with Stage T1-T3N0M0 oropharyngeal cancer were used. The clinical target volumes of the primary tumor (CTV(primary)) and of the lymph nodes (CTV(elective)) were expanded by 0.0, 1.5, 3.0, and 5.0 mm in all directions, creating the planning target volumes (PTVs). We performed IMRT dose calculation using our class solution for each PTV margin, resulting in the conventional static plans. Then, the system recalculated the plan for each positioning displacement derived from a normal distribution with sigma = 2 mm and sigma = 4 mm (standard deviation) for translational deviations and sigma = 1 degrees for rotational deviations. The dose distributions of the 30 fractions were summed, resulting in the actual plan. The CTV dose coverage of the actual plans was compared with that of the static plans. RESULTS: Random translational deviations of sigma = 2 mm and rotational deviations of sigma = 1 degrees did not affect the CTV(primary) volume receiving 95% of the prescribed dose (V(95)) regardless of the PTV margin used. A V(95) reduction of 3% and 1% for a 0.0-mm and 1.5-mm PTV margin, respectively, was observed for sigma = 4 mm. The V(95) of the CTV(elective) contralateral was approximately 1% and 5% lower than that of the static plan for sigma = 2 mm and sigma = 4 mm, respectively, and for PTV margins

Background and purpose: We are developing a technique for highly focused vocal cord irradiation in early glottic carcinoma to optimally treat a target volume confined to a single cord. This technique, in contrast with the conventional methods, aims at sparing the healthy vocal cord. As such a technique requires sub-mm daily targeting accuracy to be effective, we investigate the accuracy achievable with on-line kV-cone beam CT (CBCT) corrections. Materials and methods: CBCT scans were obtained in 10 early glottic cancer patients in each treatment fraction. The grey value registration available in X-ray volume imaging (XVI) software (Elekta, Synergy) was applied to a volume of interest encompassing the thyroid cartilage. After application of the thus derived corrections, residue displacements with respect to the planning CT scan were measured at clearly identifiable relevant landmarks. The intra- and inter-observer variations were also measured. Results: While before correction the systematic displacements of the vocal cords were as large as 2.4 +/- 3.3 mm (cranial-caudal population mean +/- SD Sigma), daily CBCT registration and correction reduced these values to less than 0.2 +/- 0.5 mm in all directions. Random positioning errors (SD sigma) were reduced to less than 1 mm. Correcting only for translations and not for rotations did not appreciably affect this accuracy. The residue random displacements partly stem from intra-observer variations (SD = 0.2-0.6 mm). Conclusion: The use of CBCT for daily image guidance in combination with standard mask fixation reduced systematic and random set-up errors of the vocal cords to

Purpose To develop and evaluate an MR sialography protocol that reproducibly images the parotid and submandibular ducts over time, in 3D. Such a protocol is needed in order to investigate the possible radiation-induced changes to the salivary ducts in patients receiving radiotherapy to the head-and-neck. Materials and Methods MR sialography was performed on a 1.5-T MR scanner. Sequence parameters were optimized on 11 healthy volunteers. A 3D water-selective turbo spin echo (TSE) pulse sequence (TR/TE = 6000 msec/190 msec), using a two-element circular surface coil was applied twice in one MR session. In order to assess the reproducibility, the same procedure was repeated four to six months later. The quality of the MR sialograms was measured subjectively by developing a visibility scoring system and objectively by the means of contrast-to-noise ratio (CNR) of the ducts vs. fat (CNRduct-fat). Results High-quality, 3D MR sialographic images were obtained. The quality of the MR sialograms and the subjective visibility score of the salivary ducts were constant over time. The CNRduct-fat varied between volunteers (standard deviation, SD 26%) but it was relatively constant per volunteer (SD 5%). Conclusion The MR sialography protocol presented in this study provides good quality 3D imaging of the major salivary ducts, submandibular duct, and the parotid duct and it can be used for the comparison of the salivary duct system of an individual over time. J. Magn. Reson. Imaging 2006. © 2006 Wiley-Liss, Inc.

Purpose To investigate the influence of the cranial border of electively irradiated Level II lymph nodes on xerostomia in patients with oropharyngeal cancer using three-dimensional conformal and intensity-modulated radiotherapy (3D-CRT and IMRT). Methods and materials The target volumes and organs at risk were delineated on the planning CT scans of 12 patients. Two elective target volumes were delineated. The first had the transverse process of the C1 atlas and the second had the transverse process of the C2 axis as cranial border of the Level II lymph nodes. 3D-CRT and IMRT planning were performed for both elective volumes, resulting in two plans per patient and technique, called the C1 and C2 plans, respectively. Irradiation of the ipsilateral elective volume up to C1 and the contralateral up to C2 was also performed for IMRT. The normal tissue complication probability (NTCP) for xerostomia 1 year after RT was calculated using the parotid mean dose. Results The average mean dose ± standard deviation (SD) to the contralateral parotid gland was reduced from 33 ± 5 Gy for the IMRT C1 plans to 26 ± 4 Gy for the IMRT C2 plans and from 51 ± 6 Gy to 49 ± 7 Gy for the 3D-CRT C1 and C2 plans, respectively. The associated NTCP ± SD for xerostomia was 38% ± 10% for IMRT C1 plans and 24% ± 6% for IMRT up to C2 on the contralateral side, regardless of which cranial border was irradiated on the ipsilateral side. For the 3D-CRT C1 and C2 plans, an NTCP value of 74% ± 12% and 71% ± 15% was obtained, respectively. The NTCP for xerostomia of the ipsilateral parotid gland was 53% ± 17% and 45% ± 20% for the IMRT C1 and C2 plans and 89% ± 11% and 87% ± 12% for the 3D-CRT C1 and C2 plans, respectively. Conclusion Lowering the cranial border of the Level II lymph nodes from C1 to C2, in the case of bilateral elective neck irradiation, could be considered on the contralateral side when the risk of metastasis on that side is very low. This is especially true when IMRT is used, because the relative reduction of NTCP for xerostomia 1 year after RT could be up to 68% compared with conventional conformal RT up to C1.

 Laryngeal cancer patients showed substantial interfraction set-up variations, including large time trends, and poor CC-correlation between primary tumor displacements and motion of the nodes and bony anatomy (internal tumor motion). These trends and non-rigid anatomy variations have to be considered in the choice of set-up verification protocol and PTV margins.  eNAL could largely compensate time trends with minor prolongation of fraction time, workload and imaging dose.  Without CBCT guided set-up corrections, generally applied 5 mm PTV margins in head and neck cancer for the primary tumor and nodes were inadequate for the studied laryngeal cancer patients. Cone-beam CT (CBCT) Guided Tumor Positioning for Laryngeal Cancer Patients with Large Interfraction Time Trends in Tumor Set-Up

Purpose We have been developing an image-guided single vocal cord irradiation technique to treat patients with stage T1a glottic carcinoma. In the present study, we compared the dose coverage to the affected vocal cord and the dose delivered to the organs at risk using conventional, intensity-modulated radiotherapy (IMRT) coplanar, and IMRT non-coplanar techniques. Methods and Materials For 10 patients, conventional treatment plans using two laterally opposed wedged 6-MV photon beams were calculated in XiO (Elekta-CMS treatment planning system). An in-house IMRT/beam angle optimization algorithm was used to obtain the coplanar and non-coplanar optimized beam angles. Using these angles, the IMRT plans were generated in Monaco (IMRT treatment planning system, Elekta-CMS) with the implemented Monte Carlo dose calculation algorithm. The organs at risk included the contralateral vocal cord, arytenoids, swallowing muscles, carotid arteries, and spinal cord. The prescription dose was 66 Gy in 33 fractions. Results For the conventional plans and coplanar and non-coplanar IMRT plans, the population-averaged mean dose ± standard deviation to the planning target volume was 67 ± 1 Gy. The contralateral vocal cord dose was reduced from 66 ± 1 Gy in the conventional plans to 39 ± 8 Gy and 36 ± 6 Gy in the coplanar and non-coplanar IMRT plans, respectively. IMRT consistently reduced the doses to the other organs at risk. Conclusions Single vocal cord irradiation with IMRT resulted in good target coverage and provided significant sparing of the critical structures. This has the potential to improve the quality-of-life outcomes after RT and maintain the same local control rates.