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Objective . Previous methods for robustness evaluation rely on dose calculation for a number of uncertainty scenarios, which either fails to provide statistical meaning when the number is too small (e.g., ∼8) or becomes unfeasible in daily clinical practice when the number is sufficiently large (e.g., >100). Our proposed deep learning (DL)-based method addressed this issue by avoiding the intermediate dose calculation step and instead directly predicting the percentile dose distribution from the nominal dose distribution using a DL model. In this study, we sought to validate this DL-based statistical robustness evaluation method for efficient and accurate robustness quantification in head and neck (H&N) intensity-modulated proton therapy with diverse beam configurations and multifield optimization. Approach . A dense, dilated 3D U-net was trained to predict the 5th and 95th percentile dose distributions of uncertainty scenarios using the nominal dose and planning CT images. The data set comprised proton therapy plans for 582 H&N cancer patients. Ground truth percentile values were estimated for each patient through 600 dose recalculations, representing randomly sampled uncertainty scenarios. The comprehensive comparisons of different models were conducted for H&N cancer patients, considering those with and without a beam mask and diverse beam configurations, including varying beam angles, couch angles, and beam numbers. The performance of our model trained based on a mixture of patients with H&N and prostate cancer was also assessed in contrast with models trained based on data specific for patients with cancer at either site. Results . The DL-based model's predictions of percentile dose distributions exhibited excellent agreement with the ground truth dose distributions. The average gamma index with 2 mm / 2%, consistently exceeded 97% for both 5th and 95th percentile dose volumes. Mean dose-volume histogram error analysis revealed that predictions from the combined training set yielded mean errors and standard deviations that were generally similar to those in the specific patient training data sets. Significance . Our proposed DL-based method for evaluation of the robustness of proton therapy plans provides precise, rapid predictions of percentile dose for a given confidence level regardless of the beam arrangement and cancer site. This versatility positions our model as a valuable tool for evaluating the robustness of proton therapy across various cancer sites., (Creative Commons Attribution license.)

Background: Combining photon or proton radiotherapy with targeted therapy shows promise for head and neck cancer (HNSCC). The poly (adenosine diphosphate [ADP]-ribose) polymerase-1/2 inhibitor niraparib targets DNA damage repair (DDR). We evaluated the effects of niraparib in combination with photons or protons, and its effects on the relative biological effectiveness (RBE) of protons, in human HNSCC cell lines., Methods: Radiosensitivity was assessed and RBE was calculated with clonogenic survival assays; unrepaired DNA double-strand breaks were evaluated using immunocytochemical analysis of 53BP1 foci., Results: Niraparib reduced colony formation in two of the four cell lines tested (P < .05), enhanced radiosensitivity in all four cell lines, delayed DDR (P < .05), and increased proton vs photon RBE., Conclusion: Niraparib enhanced the sensitivity of four HNSCC cell lines to both photons and protons and increased the RBE of protons, possibly by inhibiting DDR. Niraparib may enhance the effectiveness of both photon and proton radiotherapy for patients with HNSCC., (© 2020 Wiley Periodicals, Inc.)

Background: Proton radiotherapy (PRT) may be a less toxic alternative to photon radiotherapy (XRT) for patients with head and neck squamous cell carcinoma (HNSCC). However, the molecular responses of HNSCC cells to PRT vs XRT are unclear., Methods: Proteomics analyses of protein expression profiles by reverse-phase protein arrays were done for two human papillomavirus [HPV]-negative and two HPV+ cell lines. Expression patterns of 175 proteins involved in several signaling pathways were tested., Results: Compared with PRT, XRT tended to induce lower expression of DNA damage repair-and cell cycle arrest-related proteins and higher expression of cell survival- and proliferation-related proteins., Conclusions: Under these experimental conditions, PRT and XRT induced different protein expression and activation profiles. Further preclinical verification is needed, as are studies of tumor pathway mutations as biomarkers for choice of treatment or as radiosensitization targets to improve the response of HNSCC to PRT or XRT., (© 2019 Wiley Periodicals, Inc.)

Purpose: We aimed to determine whether multiple-CT (MCT) optimization of intensity-modulated proton therapy (IMPT) could improve plan robustness to anatomical changes and therefore reduce the additional need for adaptive planning., Methods and Materials: Ten patients with head and neck cancer who underwent IMPT were included in this retrospective study. Each patient had primary planning CT (PCT), a first adaptive planning CT (ACT1), and a second adaptive planning CT (ACT2). Selective robust IMPT plans were generated using each CT data set (PCT, ACT1, and ACT2). Moreover, a MCT optimized plan was generated using the PCT and ACT1 data sets together. Dose distributions optimized using each of the four plans (PCT, ACT1, ACT2, and MCT plans) were re-calculated on ACT2 data. The doses to the target and to organs at risk were compared between optimization strategies., Results: MCT plans for all patients met all target dose and organs-at-risk criteria for all three CT data sets. Target dose and organs-at-risk dose for PCT and ACT1 plans re-calculated on ACT2 data set were compromised, indicating the need for adaptive planning on ACT2 if PCT or ACT1 plans were used. The D 98% of CTV1 and CTV3 of MCT plan re-calculated on ACT2 were both above the coverage criteria. The CTV2 coverage of the MCT plan re-calculated on ACT2 was worse than ACT2 plan. The MCT plan re-calculated on ACT2 data set had lower chiasm, esophagus, and larynx doses than did PCT, ACT1, or ACT2 plans re-calculated on ACT2 data set., Conclusions: MCT optimization can improve plan robustness toward anatomical change and may reduce the number of plan adaptation for head and neck cancers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To assess the worst-case robust optimization IMPT plans with setup and range uncertainties and to test the hypothesis that the worst-case robust optimization strategies could cover most possible setup and range uncertainties in the real scenarios., Methods: We analyzed the nominal and worst-case robust optimization IMPT plans of seven patients with head and neck cancer patients. To take uncertainties into account for the dose calculation, we performed a comprehensive simulation in which the dose was recalculated 625 times per given plan using Gaussian systematic setup and proton range uncertainties. Subsequently, based on the simulation results, we calculated the target coverage in all perturbation scenarios, as well as the ratios of target coverage located within the threshold of eight worst-case scenarios. We set the criteria for the optimized plan to be the ratios of 1) the dose delivered to 95% (D95%) of clinical target volumes 1 and 2 (CTV1 and CTV2) above 95% of the prescribed dose, and 2) the D95% of clinical target volume 3 (CTV3) above 90% of the prescribed dose in worst-case situations., Results: The probability that the perturbed-dose indices of the CTVs in each scenario were within the worst-case scenario limits ranged from 89.51 to 91.22% for both the nominal and worst-case robust optimization IMPT plans. A quartile analysis showed that the selective robust optimization IMPT plans all had higher D95% values for CTV1, CTV2, and CTV3 than did the nominal IMPT plans., Conclusions: The worst-case strategy for robust optimization is adequately models and covers most of the setup and range uncertainties for the IMPT treatment of head and neck patients in our center.

Background: Photon (X-ray) radiotherapy (XRT) kills cells via DNA damage, however, how proton radiotherapy (PRT) causes cell death in head and neck squamous cell carcinoma (HNSCC) is unclear. We investigated mechanisms of HNSCC cell death after XRT versus PRT., Methods: We assessed type of death in 2 human papillomavirus (HPV)-positive and two HPV-negative cell lines: necrosis and apoptosis (Annexin-V fluorescein isothiocyanate [FITC]); senescence (β-galactosidase); and mitotic catastrophe (γ-tubulin and diamidino-phenylindole [DAPI])., Results: The XRT-induced or PRT-induced cellular senescence and mitotic catastrophe in all cell lines studied suggested that PRT caused cell death to a greater extent than XRT. After PRT, mitotic catastrophe peaked in HPV-negative and HPV-positive cells at 48 and 72 hours, respectively. No obvious differences were noted in the extent of cell necrosis or apoptosis after XRT versus PRT., Conclusion: Under the conditions and in the cell lines reported here, mitotic catastrophe and senescence were the major types of cell death induced by XRT and PRT, and PRT may be more effective., (© 2018 Wiley Periodicals, Inc.)

Objective: To externally validate head and neck cancer (HNC) photon-derived normal tissue complication probability (NTCP) models in patients treated with proton beam therapy (PBT)., Methods: This prospective cohort consisted of HNC patients treated with PBT at a single institution. NTCP models were selected based on the availability of data for validation and evaluated by using the leave-one-out cross-validated area under the curve (AUC) for the receiver operating characteristics curve., Results: 192 patients were included. The most prevalent tumor site was oropharynx (n=86, 45%), followed by sinonasal (n=28), nasopharyngeal (n=27) or parotid (n=27) tumors. Apart from the prediction of acute mucositis (reduction of AUC of 0.17), the models overall performed well. The validation (PBT) AUC and the published AUC were respectively 0.90 versus 0.88 for feeding tube 6months PBT; 0.70 versus 0.80 for physician-rated dysphagia 6months after PBT; 0.70 versus 0.68 for dry mouth 6months after PBT; and 0.73 versus 0.85 for hypothyroidism 12months after PBT., Conclusion: Although a drop in NTCP model performance was expected for PBT patients, the models showed robustness and remained valid. Further work is warranted, but these results support the validity of the model-based approach for selecting treatment for patients with HNC., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The primary treatment for head and neck adenoid cystic carcinoma (ACC) is surgery. Infrequently, however, ACC's propensity for perineural and base of skull invasion can preclude definitive surgical management. We present our experience with proton radiation therapy (RT) and concurrent platinum-based chemotherapy., Methods: Nine patients with unresectable node-negative, nonmetastatic head and neck ACC received definitive proton RT and concurrent cisplatin. Outcomes and toxicities were recorded. A systematic review of the literature was performed., Results: Median follow-up was 27 months (range, 9.2-48.3 months). Four patients achieved complete response at the primary site, and an additional 4 patients achieved stabilization of local disease. Only 1 patient developed local disease progression. Four patients had 5 acute grade 3 (G3) toxicities, and 1 patient developed a chronic G4 optic nerve disorder., Conclusion: Our preliminary results suggest proton RT and concurrent chemotherapy is a definitive treatment option for select patients with head and neck ACC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1472-E1480, 2016., (© 2015 Wiley Periodicals, Inc.)

Background: We report the first clinical experience and toxicity of multifield optimization (MFO) intensity modulated proton therapy (IMPT) for patients with head and neck tumors., Methods and Materials: Fifteen consecutive patients with head and neck cancer underwent MFO-IMPT with active scanning beam proton therapy. Patients with squamous cell carcinoma (SCC) had comprehensive treatment extending from the base of the skull to the clavicle. The doses for chemoradiation therapy and radiation therapy alone were 70 Gy and 66 Gy, respectively. The robustness of each treatment plan was also analyzed to evaluate sensitivity to uncertainties associated with variations in patient setup and the effect of uncertainties with proton beam range in patients. Proton beam energies during treatment ranged from 72.5 to 221.8 MeV. Spot sizes varied depending on the beam energy and depth of the target, and the scanning nozzle delivered the spot scanning treatment "spot by spot" and "layer by layer.", Results: Ten patients presented with SCC and 5 with adenoid cystic carcinoma. All 15 patients were able to complete treatment with MFO-IMPT, with no need for treatment breaks and no hospitalizations. There were no treatment-related deaths, and with a median follow-up time of 28 months (range, 20-35 months), the overall clinical complete response rate was 93.3% (95% confidence interval, 68.1%-99.8%). Xerostomia occurred in all 15 patients as follows: grade 1 in 10 patients, grade 2 in 4 patients, and grade 3 in 1 patient. Mucositis within the planning target volumes was seen during the treatment of all patients: grade 1 in 1 patient, grade 2 in 8 patients, and grade 3 in 6 patients. No patient experienced grade 2 or higher anterior oral mucositis., Conclusions: To our knowledge, this is the first clinical report of MFO-IMPT for head and neck tumors. Early clinical outcomes are encouraging and warrant further investigation of proton therapy in prospective clinical trials., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Spot-scanning proton therapy (SSPT) using multifield optimization (MFO) can generate highly conformal dose distributions, but it is more sensitive to setup and range uncertainties than SSPT using single-field optimization (SFO). The authors compared the two optimization methods for the treatment of head and neck cancer with bilateral targets and determined the superior method on the basis of both the plan quality and the plan robustness in the face of setup and range uncertainties., Methods: Four patients with head and neck cancer with bilateral targets who received SSPT treatment in the authors' institution were studied. The patients had each been treated with a MFO plan using three fields. A three-field SFO plan (3F-SFO) and a two-field SFO plan (2F-SFO) with the use of a range shifter in the beam line were retrospectively generated for each patient. The authors compared the plan quality and robustness to uncertainties of the SFO plans with the MFO plans. Robustness analysis of each plan was performed to generate the two dose distributions consisting of the highest and the lowest possible doses (worst-case doses) from the spatial and range perturbations at every voxel. Dosimetric indices from the nominal and worst-case plans were compared., Results: The 3F-SFO plans generally yielded D95 and D5 values in the targets that were similar to those of the MFO plans. 3F-SFO resulted in a lower dose to the oral cavity than MFO in all four patients by an average of 9.9 Gy, but the dose to the two parotids was on average 6.7 Gy higher for 3F-SFO than for MFO. 3F-SFO plans reduced the variations of dosimetric indices under uncertainties in the targets by 22.8% compared to the MFO plans. Variations of dosimetric indices under uncertainties in the organs at risk (OARs) varied between organs and between patients, although they were on average 9.2% less for the 3F-SFO plans than for the MFO plans. Compared with the MFO plans, the 2F-SFO plans showed a reduced dose to the parotids for both the nominal dose and in the worst-case scenario, but the plan robustness in the target of the 2F-SFO plans was not notably greater than that of the MFO plans., Conclusions: Compared with MFO, 3F-SFO improves plan robustness in the targets but degrades dose sparing in the parotids in both the nominal and worst-case scenarios. Although 2F-SFO improves parotid sparing compared with MFO, it produces little improvement in plan robustness. Therefore, considering its tolerable target coverage and sparing of OARs in worst-case scenarios, the authors recommend MFO as the planning method for the treatment of head and neck cancer with bilateral targets.

Purpose: To assess the positioning accuracy using two-dimensional kilovoltage (2DkV) imaging and three-dimensional cone beam CT (CBCT) in patients with head and neck (H&N) cancer receiving radiation therapy. To assess the benefit of patient-specific headrest., Materials and Methods: All 21 patients studied were immobilized using thermoplastic masks with either a patient-specific vacuum bag (11 of 21, IMA) or standard clear plastic (10 of 21, IMB) headrests. Each patient was imaged with a pair of orthogonal 2DkV images in treatment position using onboard imaging before the CBCT procedure. The 2DkV and CBCT images were acquired weekly during the same session. The 2DkV images were reviewed by oncologists and also analyzed by a software tool based on mutual information (MI)., Results: Ninety-eight pairs of assessable 2DkV-CBCT alignment sets were obtained. Systematic and random errors were <1.6 mm for both 2DkV and CBCT alignments. When we compared shifts determined by CBCT and 2DkV for the same patient setup, statistically significant correlations were observed in all three major directions. Among all CBCT couch shifts, 4.1% > or = 0.5 cm and 18.7% > or = 0.3 cm, whereas among all 2DkV (MI) shifts, 1.7% > or = 0.5 cm and 11.2% > or = 0.3 cm. Statistically significant difference was found on anteroposterior direction between IMA and IMB with the CBCT alignment only., Conclusions: The differences between 2D and 3D alignments were mainly caused by the relative flexibility of certain H&N structures and possibly by rotation. Better immobilization of the flexible neck is required to further reduce the setup errors for H&N patients receiving radiotherapy.

Purpose: Computed tomography (CT) streak artifacts caused by metallic implants remain a challenge for the automatic processing of image data. The impact of metal artifacts in the soft-tissue region is magnified in cone-beam CT (CBCT), because the soft-tissue contrast is usually lower in CBCT images. The goal of this study was to develop an effective offline processing technique to minimize the effect., Methods and Materials: The geometry calibration cue of the CBCT system was used to track the position of the metal object in projection views. The three-dimensional (3D) representation of the object can be established from only two user-selected viewing angles. The position of the shadowed region in other views can be tracked by projecting the 3D coordinates of the object. Automatic image segmentation was used followed by a Laplacian diffusion method to replace the pixels inside the metal object with the boundary pixels. The modified projection data were then used to reconstruct a new CBCT image. The procedure was tested in phantoms, prostate cancer patients with implanted gold markers and metal prosthesis, and a head-and-neck patient with dental amalgam in the teeth., Results: Both phantom and patient studies demonstrated that the procedure was able to minimize the metal artifacts. Soft-tissue visibility was improved near or away from the metal object. The processing time was 1-2 s per projection., Conclusion: We have implemented an effective metal artifact-suppressing algorithm to improve the quality of CBCT images.

Purpose: The purpose of this study is to evaluate the impact of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) fused with planning computed tomography (CT) on tumor localization, which guided intensity-modulated radiotherapy (IMRT) of patients with head-and-neck carcinoma., Methods and Materials: From October 2002 through April 2005, we performed FDG-PET/CT guided IMRT for 28 patients with head-and-neck carcinoma. Patients were immobilized with face masks that were attached with five fiducial markers. FDG-PET and planning CT scans were performed on the same flattop table in one session and were then fused. Target volumes and critical organs were contoured, and IMRT plans were generated based on the fused images., Results: All 28 patients had abnormal increased uptake in FDG-PET/CT scans. PET/CT resulted in CT-based staging changes in 16 of 28 (57%) patients. PET/CT fusions were successfully performed and were found to be accurate with the use of the two commercial planning systems. Volume analysis revealed that the PET/CT-based gross target volumes (GTVs) were significantly different from those contoured from the CT scans alone in 14 of 16 patients. In addition, 16 of 28 patients who were followed for more than 6 months did not have any evidence of locoregional recurrence in the median time of 17 months., Conclusion: Fused images were found to be useful to delineate GTV required in IMRT planning. PET/CT should be considered for both initial staging and treatment planning in patients with head-and-neck carcinoma.

Purpose: To analyze three-dimensional setup uncertainties for multiple regions of interest (ROIs) in head-and-neck region., Methods and Materials: In-room computed tomography (CT) scans were acquired using a CT-on-rails system for 14 patients. Three separate bony ROIs were defined: C2 and C6 vertebral bodies and the palatine process of the maxilla. Translational shifts of 3 ROIs were calculated relative to the marked isocenter on the immobilization mask., Results: The shifts for all 3 ROIs were highly correlated. However, noticeable differences on the order of 2-6 mm existed between any 2 ROIs, indicating the flexibility and/or rotational effect in the head-and-neck region. The palatine process of the maxilla had the smallest right-left shifts because of the tight lateral fit in the face mask, but the largest superior-inferior movement because of in-plane rotation and variations in jaw positions. The neck region (C6) had the largest right-left shifts. The positioning mouthpiece was found effective in reducing variations in the superior-inferior direction. There was no statistically significant improvement for using the S-board (8 out of 14 patients) vs. the short face mask., Conclusions: We found variability in setup corrections for different regions of head-and-neck anatomy. These relative positional variations should be considered when making setup corrections or designing treatment margins.