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Background/aim: The current study aimed to evaluate a treatment planning method that is robust against tumor growth and to assess its effectiveness in particle therapy for head and neck cancer., Patients and Methods: The proposed method optimizes dose distribution by replacing the relative stopping power ratio (rSPR) of the clinical target volume (CTV) cavity region with a tumor-equivalent rSPR (Condition 1). The optimized initial treatment plan template was then recalculated using in-room CT images acquired in the same treatment position, and the doses to the tumor and organs at risk were compared with those in the initial treatment plan. We evaluated this method in 10 patients with head and neck cancer treated with carbon ion radiotherapy. To evaluate the effectiveness of the proposed method, we compared it to the initial treatment plan without the replacement (Condition 2)., Results: CTV V95% reduction relative to that of the initial treatment plan at the end of treatment was 1.3%±2.9% and 2.6%±3.7% for Condition 1 and Condition 2, respectively, with Condition 1 (Replacement condition) providing better CTV coverage. Subgroup analysis showed a higher change in target coverage in the mucosal melanoma than in the adenoid cystic carcinoma, suggesting that this was influenced by the rate of tumor growth., Conclusion: The proposed treatment planning method, which adjusts for tumor growth by modifying the rSPR in the cavity region, improved robustness in carbon ion radiotherapy for head and neck cancer. Condition 1 (with replacement) achieved better CTV coverage than Condition 2 (without replacement), particularly in fast-growing tumors like mucosal melanoma. This method ensures consistent dose delivery to tumors while maintaining safe doses to organs at risk, offering potential for improved treatment outcomes., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: This study aimed to compare the effects of a mobile health intervention based on social cognitive theory with standard care on maximal mouth opening, exercise compliance, and self-efficacy in patients receiving proton and heavy ion therapy for head and neck cancer., Methods: This open-label, parallel-group, randomized, superiority trial involved a self-developed "Health Enjoy System" intervention. We assessed maximal mouth opening, exercise compliance, and self-efficacy at baseline (T 0 ), post-treatment (T 1 ), and at 1 month (T 2 ) and 3 months (T 3 ) after radiotherapy. Generalized estimating equations were used to analyze differences between the groups over time, with results reported as P values and 95% confidence intervals (CIs)., Results: The study included 44 participants. At T 3 , the intervention group showed a 6 mm greater increase in maximal interincisal opening than the control group (mean difference = 6.0, 95% CI = 2.4 to 9.5, P = 0.001). There was also a significant difference in exercise compliance between the groups (mean difference = 31.7, 95% CI = 4.6 to 58.8, P = 0.022). However, no significant difference in self-efficacy was found between the groups., Conclusion: This study demonstrated that an mHealth intervention incorporating behavior change theory could effectively enhance or maintain maximal mouth opening in patients undergoing proton and heavy ion therapy for head and neck cancer in China. This approach provides valuable support during and after treatment., Trial Registration: ChiCTR: ChiCTR2300067550. Registered 11 Jan 2023., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This feasibility study confirmed the initial safety and efficacy of a novel carbon-ion radiotherapy (CIRT) using linear energy transfer (LET) painting for head and neck cancer. This study is the first step toward establishing CIRT with LET painting in clinical practice and making it a standard practice in the future., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Head and neck adenoid cystic carcinoma (HNACC) is a radioresistant tumor. Particle therapy, primarily proton beam therapy and carbon-ion radiation, is a potential radiotherapy treatment for radioresistant malignancies. This study aims to conduct a meta-analysis to evaluate the impact of charged particle radiation therapy on HNACC. Methods: A comprehensive search was conducted in Pubmed, Cochrane Library, Web of Science, Embase, and Medline until December 31, 2022. The primary endpoints were overall survival (OS), local control (LC), and progression-free survival (PFS), while secondary outcomes included treatment-related toxicity. Version 17.0 of STATA was used for all analyses. Results: A total of 14 studies, involving 1297 patients, were included in the analysis. The pooled 5-year OS and PFS rates for primary HNACC were 78% (95% confidence interval [CI] = 66-91%) and 62% (95% CI = 47-77%), respectively. For all patients included, the pooled 2-year and 5-year OS, LC, and PFS rates were as follows: 86.1% (95% CI = 95-100%) and 77% (95% CI = 73-82%), 92% (95% CI = 84-100%) and 73% (95% CI = 61-85%), and 76% (95% CI = 68-84%) and 55% (95% CI = 48-62%), respectively. The rates of grade 3 and above acute toxicity were 22% (95% CI = 13-32%), while late toxicity rates were 8% (95% CI = 3-13%). Conclusions: Particle therapy has the potential to improve treatment outcomes and raise the quality of life for HNACC patients. However, further research and optimization are needed due to the limited availability and cost considerations associated with this treatment modality., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: This study aimed to compare the results of irradiation with protons versus irradiation with carbon ions in a raster scan technique in patients with skull base chordomas and to identify risk factors that may compromise treatment results., Methods: A total of 147 patients (85 men, 62 women) were irradiated with carbon ions (111 patients) or protons (36 patients) with a median dose of 66 Gy (RBE (Relative biological effectiveness); carbon ions) in 4 weeks or 74 Gy (RBE; protons) in 7 weeks at the Heidelberg Ion Beam Therapy Center (HIT) in Heidelberg, Germany. The median follow-up time was 49.3 months. All patients had gross residual disease at the beginning of RT. Compression of the brainstem was present in 38%, contact without compression in 18%, and no contact but less than 3 mm distance in 16%. Local control and overall survival were evaluated using the Kaplan-Meier Method based on scheduled treatment (protons vs. carbon ions) and compared via the log rank test. Subgroup analyses were performed to identify possible prognostic factors., Results: During the follow-up, 41 patients (27.9%) developed a local recurrence. The median follow-up time was 49.3 months (95% CI: 40.8-53.8; reverse Kaplan-Meier median follow-up time 56.3 months, 95% CI: 51.9-60.7). No significant differences between protons and carbon ions were observed regarding LC, OS, or overall toxicity. The 1‑year, 3‑year, and 5‑year LC rates were 97%, 80%, and 61% (protons) and 96%, 80%, and 65% (carbon ions), respectively. The corresponding OS rates were 100%, 92%, and 92% (protons) and 99%, 91%, and 83% (carbon ions). No significant prognostic factors for LC or OS could be determined regarding the whole cohort; however, a significantly improved LC could be observed if the tumor was > 3 mm distant from the brainstem in patients presenting in a primary situation., Conclusion: Outcomes of proton and carbon ion treatment of skull base chordomas seem similar regarding tumor control, survival, and toxicity. Close proximity to the brainstem might be a negative prognostic factor, at least in patients presenting in a primary situation., (© 2022. The Author(s).)

Purpose: The goal of this multicenter retrospective study of patients with head and neck malignancies was to evaluate the efficacy and safety of carbon-ion (C-ion) radiotherapy (RT) after photon RT., Methods: We enrolled 56 patients with head and neck malignancies who underwent re-irradiation (re-RT) using C-ions between November 2003 and March 2019, treated previously with photon RT. The tumors at re-RT were located in the sinonasal cavities (n = 20, 35.7%), skull base (n = 12, 21.4%), and orbit (n = 7, 12.5%). The tumors at the initial RT were located in the sinonasal cavities (n = 13, 23.2%), skull base (n = 9, 16.1%), and orbit (n = 9, 16.1%). The median period between the initial RT and re-RT was 41 (4-568) months. The most common histology of re-RT was squamous cell carcinoma (n = 11, 19.6%). The most commonly used protocol was 57.6 Gy (relative biological effectiveness) in 16 fractions (n = 23, 41.1%). Surgery preceded re-RT in three patients (5.4%). One patient with malignant melanoma received concurrent chemotherapy., Results: The 2-year local control, progression-free survival, and overall survival rates were 66.5%, 36.9%, and 67.9%, respectively. The median follow-up time was 28 months. Two patients (3.6%) developed grade ≥ 3 acute toxicities, and 14 (25.0%) developed grade ≥ 3 late toxicities. A single patient had confirmed grade 5 dermatitis with infection., Conclusion: Re-RT using C-ions for head and neck malignancies after photon RT is an effective treatment with tolerable toxicity., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Adenoid cystic carcinoma is a rare form of head and neck cancer with a slow, but aggressive growth pattern which remains a challenge for local tumor control. Based on phase II data, radiation treatment using partially high LET radiation results in a prolonged PFS and OS. There is a paucity of randomized clinical data examining the role of the use of high LET radiation only. Therefore, the purpose of this prospective clinical trial is to analyze local control rates in patients with node negative ACC treated with carbon ion radiotherapy alone compared to a combined modality approach., Methods: This trial is conducted as a prospective, open-label, phase II, two-armed, investigator-initiated study comparing the local control rates in node negative ACCs of the head and neck treated either with sole carbon ion radiotherapy or a combination of carbon ions and photons. Secondary outcomes investigated are progression-free survival, overall survival, acute and late toxicity, and quality of life. A total of 314 patients will be randomly assigned to C12 treatment alone or bimodal treatment: Patients in the experimental group will receive a dose of 51 Gy (RBE) in 17 fractions and a boost of 15 Gy (RBE) in 5 fractions. Patients in the control group will receive 25 fractions photon IMRT 50Gy and a boost using 8 × 3 Gy (RBE) carbon ions. Local control will be assessed in regular follow up examinations until 5 years after the completion of treatment., Discussion: The present trial aims to evaluate local control rates to compare sole carbon ion radiotherapy to bimodal radiotherapy with carbon ions and photons in patients with node negative ACCs of the head and neck region. Local control is selected as the primary endpoint due to its major clinical relevance because of slow but aggressive growth patterns., Trial Registration: The study was prospectively registered on 2nd January 2020: ClinicalTrials.gov, NCT04214366 . "Adenoid Cystic Carcinoma and Carbon Ion Only Irradiation (ACCO)"., Study Status: Under recruitment, participant recruitment is not completed. Start of recruitment was January 2020. There are no results been published or submitted to any journal., (© 2021. The Author(s).)

Background: Intensity-modulated re-radiotherapy (reIMRT) has been established as a standard local treatment option in patients with non-resectable, recurrent head and neck cancer (rHNC). However, the clinical outcome is unfavorable and severe toxicities (≥grade III) occurred in 30-40% of patients. The primary aim of the current trial is to investigate carbon ion reirradiation (reCIRT) compared to reIMRT in patients with rHNC regarding safety/toxicity as well as local control, overall survival (OS), and quality of life (QoL)., Methods: The present trial will be performed as a single center, two-armed, prospective phase II study. A maximum of 72 patients will be treated with either reIMRT or reCIRT to evaluate severe (≥grade III) treatment-related toxicities (randomization ratio 1:1). The primary target value is to generate less than 35% acute/subacute severe toxicity (≥grade III), according to the Common Terminology Criteria for Adverse Events v5.0, within 6 months after study treatment. The total dose of reirradiation will range between 51 and 60 Gy or Gy (RBE), depending primarily on the radiotherapy interval and the cumulative dose to organs at risk. Individual dose prescription will be at the discretion of the treating radiation oncologist. The local and distant progression-free survival 12 months after reirradiation, the OS, and the QoL are the secondary endpoints of the trial. Explorative trial objectives are the longitudinal investigation of clinical patient-related parameters, tumor parameters on radiological imaging, and blood-based tumor analytics., Discussion: Recent retrospective studies suggested that reCIRT could represent a feasible and effective treatment modality for rHNC. This current randomized prospective trial is the first to investigate the toxicity and clinical outcome of reCIRT compared to reIMRT in patients with rHNC., Trial Registration: ClinicalTrials.gov ; NCT04185974 ; December 4th 2019.

Re-irradiation can offer a potentially curative solution in case of progression after initial therapy; however, a second course of radiotherapy can be associated with an increased risk of severe side-effects. Particle therapy with protons and especially carbon ions spares surrounding tissue better than most photon techniques, thus it is of high potential for re-irradiation. Irradiation of tumors of the brain, head and neck and skull base involves several delicate risk organs, e.g. optic system, brainstem, salivary gland or swallowing muscles. Adequate local control rates with tolerable side-effects have been described for several tumors of these locations as meningioma, adenoid cystic carcinoma, chordoma or chondrosarcoma and head and neck tumors. High life time doses nonetheless lead to a different scope of side-effects, e.g . an enhanced rate of carotid blow outs has been reported. This review summarizes the current data on particle irradiation of the aforementioned locations and malignancies.

This study aimed to evaluate the efficacy of carbon-ion radiotherapy in combination with chemotherapy using dacarbazine, nimustine, and vincristine (DAV therapy) in mucosal melanoma. Twenty-one patients with clinically localized mucosal melanoma of the head and neck were enrolled. The primary endpoint was 3-year overall survival (OS). Secondary endpoints included local control, progression-free survival (PFS), and adverse event occurrence. Carbon-ion radiotherapy with a dose of 57.6-64.0 Gy (relative biological effectiveness) in 16 fractions was delivered concurrently with DAV therapy, and 2 cycles of adjuvant DAV therapy were administered every 6 weeks. The median follow-up periods were 15.5 months for all patients, and 31.2 months for 12 surviving patients. All patients had locally advanced T4a or T4b disease in the rhino-sinus area. In 16 patients (76.2%), 3 cycles of planned DAV therapy were completed. The 3-year OS and PFS rates were 49.2% and 37.0% respectively. The 3-year local control rate was 92.3%. Eleven patients (52%) developed distant metastasis, which was the most frequent pattern of the first failure. Commonly presenting acute grade 2-3 toxicities associated with radiotherapy and chemotherapy were mucositis (11 patients [53%]) and leukopenia (9 patients [43%]), which improved with conservative therapy. None of the patients developed grade 3 or greater late toxicities. Carbon-ion radiotherapy in combination with DAV therapy led to excellent local control for advanced mucosal melanoma within acceptable toxicities. The efficacy of additional DAV therapy in improving survival was weaker than expected as distant metastases still occurred frequently. Trial registration no. UMIN000007939., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: This study aimed to assess the feasibility of carbon ion reirradiation (CIR) for recurrent head and neck cancer (HNC)., Methods and Materials: This retrospective study included 229 patients with recurrent HNC who were treated with CIR between 2010 and 2017. We assessed progression-free survival, overall survival, pattern of failure, and toxicity. Of the primary tumors, 54.1% were adenoid cystic carcinomas, 26.2% were squamous cell carcinomas, 8.3% were adenocarcinomas, and 11.4% were other tumor entities., Results: The median radiation therapy interval was 3.9 years (range, 0.3-46.5 years), and patients received a median dose of 51 Gy (relative biological effectiveness [RBE]; range, 30-66 Gy [RBE]) in 3 Gy (RBE) fractions. The median cumulative lifetime dose after CIR was 132.8 Gy (range, 88.8-155.0 Gy). The median local progression-free survival after CIR was 24.2 months (95% confidence interval, 19.4-29.0 months), and the median overall survival was 26.1 months (95% confidence interval, 21.9-30.3 months). Serious acute toxicity (grade ≥3) after CIR included laryngeal edema, grade 4 (n = 2; 0.9%); dysphagia, grade 3 (n = 3; 1.3%); fistula, grade 3 (n = 1; 0.4%); and impaired hearing, grade 3 (n = 1; 0.4%). Late toxicities of grades 3 or higher (n = 18; 14.5%) included central nervous system necrosis, grades 4/3 (n = 1; 0.8%/n = 5; 4.0%); optic nerve disorder, grades 4/3 (n = 2; 1.6%/n = 2; 1.6%); impaired hearing, grade 3 (n = 5; 4.0%), osteonecrosis, grade 3 (n = 1; 0.8%); and carotid blowout, grade 4 (n = 1; 0.8%)., Conclusions: In patients with locally recurrent HNC, CIR was a feasible, effective treatment with acceptable toxicity and good local control. Thus, CIR represented a valuable alternative to surgical salvage and palliative chemotherapy in selected patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The objective of this investigation is to evaluate the outcomes and toxicity of carbon-ion re-irradiation (CIR) in patients with rare head and neck cancers (HNC). There is a paucity of data regarding treatment approaches in this patient cohort, which we aim to address in this work., Methods: Thirty-two (n = 32) consecutive patients with uncommon HNC treated between 2010 and 2017 were retrospectively analyzed in terms of clinical outcomes, patterns of failure, and toxicity., Results: Mucoepidermoid carcinoma (MEC) was the most common histology (22%). Patients received a median cumulative dose equivalent in 2 Gy fractions (EQD 2 ) after CIR of 128.6 Gy (range, 105.8-146.5 Gy). The local and distant control rates 1 year after CIR were 66 and 72%. No serious acute or late toxicity (≥ grade 3) after CIR was observed., Conclusions: CIR may represent an effective and safe treatment alternative to palliative systemic therapies in these rare indications.

Objective: We had developed compact rotating gantry for carbon ion using superconducting magnets in 2015 which became clinically operational in 2017. The objective of this study was to assess the clinical feasibility and safety of using compact rotating gantry with three-dimensional active scanning in delivery of carbon-ion radiotherapy (C-ion RT) for relatively stationary tumours., Methods: A prospective feasibility study was conducted with 10 patients who had been treated with C-ion RT using compact rotating gantry between April 2017 and April 2018 at Hospital of the National Institute of Radiological Sciences (NIRS) for head and neck and prostate cancers. The primary end point was evaluation of acute toxicities within 3 months of starting C-ion RT., Results: Out of 10 cases 8 were of head and neck cancers and 2 were of prostate cancers. All of those eight head and neck cases were of locally advanced stages. Both of the prostate cancer patients belong to intermediate risk categories. None of the patients developed even Grade 2 or more severe skin reactions. Six out of eight cases with head and neck cancers experienced Grade 2 mucosal reactions; however, nobody developed Grade 3 or more severe mucosal reactions. There was no gastrointestinal reaction observed in prostate cancer patients. One patient developed Grade 2 genitourinary reaction., Conclusion: C-ion RT using compact rotating gantry and three-dimensional active scanning is a safe and feasible treatment for relatively less mobile tumours., Advances in Knowledge: This study will be the first step to establish the use of superconducting rotating gantry in C-ionRT in clinical setting paving the way for treating large number of patients and make it a standard of practice in the future.

Purpose: We report our experience of intensity-modulated proton and carbon-ion radiotherapy (IMPT/IMCT) for head and neck sarcomas (HNS)., Methods and Materials: An analysis of the ongoing prospective data registry from the Shanghai Proton and Heavy Ion Center (SPHIC) for patients with HNS was conducted. The 12- and 24-month rates of local recurrence-free, overall, distant metastasis-free, progression-free survival (LRFS, OS, DMFS, and PFS), and acute/late toxicities were calculated. The prognostic factors for the effectiveness of the treatment were also analyzed., Results: Between 7/2014 and 5/2018, 51 consecutive patients with HNS received definitive doses of IMCT (41 cases), IMPT (two cases), or their combination (eight cases). One patient had R0 resection and another treated on the Chinese Food and Drug Administration registration trial received IMPT only. Twenty-seven patients were treated according to various dose escalation trials or institutional protocols using IMCT or IMPT + IMCT boost. Twenty-two patients with locoregional recurrence (10 and four patients failed surgery or surgery followed by radiotherapy, respectively) or radiation-induced second primary sarcomas (eight patients) received salvage particle radiotherapy. With a median follow-up time of 15.7 months, four patients with second primary sarcoma died. The 1- and 2-year OS, PFS, LRFS, and DMFS rates for the entire cohort were 92.9% vs 90%, 73.6% vs 57.4%, 88.4% vs 78.9%, and 84.6% vs 76.5%, respectively. Those rates for patients without prior radiotherapy were 100% vs 100%, 82.1% vs 65.8%, 93.6% vs 85.3%, and 88.4% vs 79.5%, respectively. Multivariate analyses revealed that re-irradiation was an independent prognostic factor for both LRFS and PFS (P = 0.015 and 0.037, respectively). In addition, gross tumor volume (GTV) was an independent prognostic factor for PFS (P = 0.048). One patient experienced Grade 3 acute toxicity (oral mucositis); another experienced Grade 4 acute event (hemorrhage) which required embolization. He lately died from hemorrhage (Grade 5) at 3.4 months after the completion of treatment. No patient experienced radiation-induced acute/late toxicity of ≥ Grade 2 otherwise., Conclusion: With few observed acute/late toxicities, IMPT/IMCT provided effective short-term tumor control in our patients with HNS. Further investigations, preferably in a prospective fashion, will be required to confirm the efficacy and toxicities of IMPT/IMCT in this group of patients., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

While Monte Carlo (MC) codes are considered as the gold standard for dosimetric calculations, the availability of user friendly MC codes suited for particle therapy is limited. Based on the FLUKA MC code and its graphical user interface (GUI) Flair, we developed an easy-to-use tool which enables simple and reliable simulations for particle therapy. In this paper we provide an overview of functionalities of the tool and with the presented clinical, proton and carbon ion therapy examples we demonstrate its reliability and the usability in the clinical environment and show its flexibility for research purposes. The first, easy-to-use FLUKA MC platform for particle therapy with GUI functionalities allows a user with a minimal effort and reduced knowledge about MC details to apply MC at their facility and is expected to enhance the popularity of the MC for both research and clinical quality assurance and commissioning purposes.

To investigate the safety and efficacy of salvage carbon-ion radiation therapy (CIRT) in patients with locoregionally recurrent head and neck malignancies. One hundred and forty-one patients with locally recurrent head and neck malignancies previously treated with radiotherapy were salvaged using intensity-modulated carbon-ion radiation therapy (CIRT). The median dose was 60 Gray-Equivalent (GyE) (range 50-69 GyE, 2.0~3.5 GyE/daily fraction). All patients completed planned CIRT except for one. With a median follow-up time of 14.7 (range 1.6-36.4) months, the 1-year overall survival rate was 95.9%. Local, regional, and distant progression free survival rates were 84.9% and 97.7%, and 96%, respectively. Grade 3 or higher acute and late toxicities were observed in 7.1% of the patients. Ten patients developed mucosal necrosis and 4 of these patients deceased. Due to its physical and biological characteristics, CIRT appeared to be an acceptable treatment option for patients with locoregionally recurrent head and neck malignancies after previous radiotherapy. Treatment-induced adverse effects and early response to CIRT were both favorable. Longer follow-up is needed to evaluate the long-term outcome in terms of disease control, survival, as well as potential late effects.

Dose and range verification have become important tools to bring carbon ion therapy to a higher level of confidence in clinical applications. Positron emission tomography is among the most commonly used approaches for this purpose and relies on the creation of positron emitting nuclei in nuclear interactions of the primary ions with tissue. Predictions of these positron emitter distributions are usually obtained from time-consuming Monte Carlo simulations or measurements from previous treatment fractions, and their comparison to the current, measured image allows for treatment verification. Still, a direct comparison of planned and delivered dose would be highly desirable, since the dose is the quantity of interest in radiation therapy and its confirmation improves quality assurance in carbon ion therapy. In this work, we present a deconvolution approach to predict dose distributions from PET images in carbon ion therapy. Under the assumption that the one-dimensional PET distribution is described by a convolution of the depth dose distribution and a filter kernel, an evolutionary algorithm is introduced to perform the reverse step and predict the depth dose distribution from a measured PET distribution. Filter kernels are obtained from either a library or are created for any given situation on-the-fly, using predictions of the [Formula: see text]-decay and depth dose distributions, and the very same evolutionary algorithm. The applicability of this approach is demonstrated for monoenergetic and polyenergetic carbon ion irradiation of homogeneous and heterogeneous solid phantoms as well as a patient computed tomography image, using Monte Carlo simulated distributions and measured in-beam PET data. Carbon ion ranges are predicted within less than 0.5 mm and 1 mm deviation for simulated and measured distributions, respectively.

Purpose: To retrospectively analyze the treatment outcomes of carbon-ion radiation therapy for adenoid cystic carcinoma (ACC) of the head and neck at 4 active carbon-ion facilities in Japan., Methods and Materials: A total of 289 patients who underwent carbon-ion radiation therapy for histology-proven ACC of the head and neck at 4 institutions in Japan between November 2003 and December 2014 were included in this study., Results: Median patient age was 58 years (range, 12-83 years). Tumor sites included the nasal cavity and paranasal sinuses (42%), nasopharynx and oropharynx (19%), oral cavity (12%), major salivary glands (12%), and others (15%). Tumor classifications were T4 in 200 (69%) patients, T3 in 45 (16%), T2 in 22 (8%), T1 in 15 (5%), and unclassified in 7 (2%). The median total dose was 64 Gy (relative biological effectiveness [RBE]; range, 55.2-70.4 Gy [RBE]) in 16 fractions (range, 12-32 fractions). Median follow-up time was 30 months (range, 2-118 months). The 2-year overall survival, progression-free survival, and local control rates were 94%, 68%, and 88%, respectively. Estimated 5-year overall survival, progression-free survival, and local control rates were 74%, 44%, and 68%, respectively. In all, 43 patients (15%) experienced grade ≥3 late toxicity, of which osteonecrosis of the jaw bone was the most common. Two patients treated for nasopharyngeal ACC died from a bleeding ulcer at the tumor site (grade 5 toxicity)., Conclusions: Carbon-ion radiation therapy seems to be a promising treatment for ACC of the head and neck., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To verify the safety and efficacy of IONTRIS particle therapy system (IONTRIS) in clinical implementation. Methods: Between 6.2014 and 8.2014, a total of 35 patients were enrolled into this trial: 31 males and 4 females with a median age of 69 yrs (range 39-80). Ten patients had locally recurrent head and neck tumors after surgery, 4 cases with thoracic malignancies, 1 case with hepatocellular carcinoma, 1 case with retroperitoneal sarcoma, and 19 cases with non-metastatic prostate carcinomas. Phantom dose verification was mandatory for each field before the start of radiation. Results: Twenty-two patients received carbon ion and 13 had proton irradiation. With a median follow-up time of 1 year, all patients were alive. Among the 16 patients with head and neck, thoracic, and abdominal/pelvic tumors, 2, 1, 12, and 1 cases developed complete response, partial response, stable disease, or disease progression, respectively. Progression-free survival rate was 93.8% (15/16). Among the 19 patients with prostate cancer, biological-recurrence free survival was 100%. Particle therapy was well tolerated in all 35 patients. Twenty-five patients (71.4%) experienced 33 grade 1 acute adverse effects, which subsided at 1 year follow-up. Six (17.1%) patients developed grade 1 late adverse effects. No significant change in ECOG or body weight was observed. Conclusions: IONTRIS is safe and effective for clinical use. However, long term follow-up is needed to observe the late toxicity and long term result.

Purpose: Head and neck (HN) adenocarcinoma is rare, and to date, there have been no reports of prospective studies. We retrospectively evaluated the efficacy and safety of carbon-ion radiation therapy (C-ion RT) for HN adenocarcinoma in institutions in Japan., Methods and Materials: HN adenocarcinoma patients with N0M0 or N1M0 disease who were treated with C-ion RT at institutions in Japan between November 2003 and December 2014 were analyzed retrospectively. We enrolled 47 patients (30 male and 17 female patients; median age, 60 years) with HN adenocarcinoma., Results: Primary sites included the nasal and paranasal sinus in 21 patients, orbit in 11, salivary grand in 7, oral cavity and pharynx in 6, and acoustic organ in 2. Thirty-two patients had T4 tumors, 6 had T3, and 6 had T2. Forty-five patients received a diagnosis of N0 disease, whereas 2 had N1 disease. The median total dose of C-ion RT and the number of fractions were 64.0 Gy (relative biological effectiveness) and 16 fractions, respectively. The median follow-up period was 51 months (range, 6-118 months). The 2- and 5-year overall survival rates were 87.9% and 60.4%, respectively, and the 2- and 5-year local control rates were 83.3% and 79.3%, respectively. Multivariate analysis showed that operability (patients with operable tumors) (P=.045) and fractionation (16 fractions) (P=.010) were significant independent prognostic factors for better overall survival. No grade 5 late morbidities were observed. Grade 4 late morbidities were observed in 4 patients, and all of these grade 4 morbidities were visual impairments. All 4 patients with grade 4 visual impairment had T4 tumors in the nasopharynx or paranasal sinuses, which implied inoperable tumors with orbital or brain invasion., Conclusions: C-ion RT resulted in excellent local control. C-ion RT could become a curative treatment option for HN adenocarcinoma with acceptable toxicities., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of this study was to determine whether l-methyl-[ 11 C]-methionine (MET) positron emission tomography (PET) allows the prediction of outcomes in patients with head and neck mucosal malignant melanoma treated with carbon ion radiation therapy (CIRT). This was a retrospective cohort study involving 85 patients who underwent a MET-PET or MET-PET/computed tomography (CT) examination before and after CIRT. MET uptake in the tumour was evaluated semi-quantitatively using the tumour-to-normal tissue ratio (TNR). Local recurrence, metastasis, and outcome predictions were studied in terms of TNR before CIRT (TNRpre), TNR after CIRT (TNRpost), and the TNR change ratio. Kaplan-Meier curves revealed significant differences between patients with higher TNRpre values and those with lower TNRpre values in regard to local recurrence, metastasis, and outcome (log-rank test P<0.0001 for all three). There were also significant differences in metastasis rates and outcomes between patients with higher and lower TNRpost values (log-rank test P=0.0105 and P=0.027, respectively). The Cox proportional hazards model revealed TNRpre to be a factor significantly influencing the risk of local recurrence (hazard ratio (HR) 29.0, P<0.001), risk of metastasis (HR 2.67, P=0.024), and the outcome (HR 6.3, P<0.001). MET-PET or MET-PET/CT is useful for predicting the outcomes of patients with head and neck mucosal malignant melanoma treated with CIRT., (Copyright © 2017. Published by Elsevier Ltd.)

Purpose: The aim of this study was to evaluate the effect of histological subtypes of head and neck adenoid cystic carcinoma (ACC) on the results of carbon-ion radiotherapy (CIRT)., Material and Methods: Of the 113 patients with ACC who were treated with CIRT between December 2006 and July 2013, 100 patients with identified histological subtypes were enrolled in this study. CIRT at a total dose of 57.6 or 64.0Gy (RBE) was administered in 16 fractions. Histological grading was defined as the presence or absence of a solid growth pattern., Results: Median follow-up was 60 months. 5-Year local control (LC), overall survival (OS) and distant metastasis free survival (DMFS) of all patients were 68.6%, 74.8% and 65.7%, respectively. On multivariate analysis, the prescribed dose (p=0.001) and gross tumor volume (p=0.002) were significant independent risk factors for LC. No significant difference for local control of solid/non-solid growth patterns was found (p=0.093). Solid growth pattern was an independent risk factor for both OS (p=0.033) and DMFS (p=0.024)., Conclusions: CIRT appears able to locally control solid growth pattern ACC in the head and neck. Improved intervention is needed to extend DMFS and OS., (Copyright © 2017. Published by Elsevier B.V.)

Background and Purpose: In this multicentric in silico trial we compared photon, proton, and carbon-ion radiotherapy plans for re-irradiation of patients with squamous cell carcinoma of the head and neck (HNSCC) regarding dose to tumour and doses to surrounding organs at risk (OARs)., Material and Methods: Twenty-five HNSCC patients with a second new or recurrent cancer after previous irradiation (70Gy) were included. Intensity-modulated proton therapy (IMPT) and ion therapy (IMIT) re-irradiation plans to a second subsequent dose of 70Gy were compared to photon therapy delivered with volumetric modulated arc therapy (VMAT)., Results: When comparing IMIT and IMPT to VMAT, the mean dose to all investigated 22 OARs was significantly reduced for IMIT and to 15 out of 22 OARs (68%) using IMPT. The maximum dose to 2% volume (D 2 ) of the brainstem and spinal cord were significantly reduced using IMPT and IMIT compared to VMAT. The data are available on www.cancerdata.org., Conclusions: In this ROCOCO in silico trial, a reduction in mean dose to OARs was achieved using particle therapy compared to photons in the re-irradiation of HNSCC. There was a dosimetric benefit favouring carbon-ions above proton therapy. These dose reductions may potentially translate into lower severe complication rates related to the re-irradiation., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: One approach to improving image quality of CT is to use metal artefact reduction image processing, such as single-energy metal artefact reduction (SEMAR). To quantify the impact of image correction on the quality of carbon-ion dose distribution, treatment planning using SEMAR was evaluated., Methods: Using a head phantom into which metal screws could be inserted, we acquired standard planning CT images. We calculated dose distributions using phantom images with and without metal added, and with and without SEMAR. Hounsfield unit (HU) and dose distribution variation of these images with and without SEMAR were measured using metal-free image subtraction. We similarly analysed the image data sets of two patients with head and neck cancer who had dental implants., Results: HU difference between metal-containing images and metal-free images without and with SEMAR were -79.5 ± 97.2 HU and -1.4 ± 19.5 HU on severe artefact area, respectively. The range of dose distribution difference from the prescribed dose between uncorrected and SEMAR-corrected images varied from -19.5% to -3.4% within planning target volume (PTV). PTV-D95 (%) for uncorrected and SEMAR-corrected image data were 82.4% and 95.4%, respectively. For data in patients with metal dental work, PTV-D95 (%) for uncorrected and SEMAR-corrected data were 92.2% and 92.5% (Patient 1), and 90.9% and 95.7% (Patient 2), respectively., Conclusion: SEMAR algorithm shows promise in improving CT image quality and in ensuring an accurate representation of dose distribution., Advances in Knowledge: SEMAR may improve treatment accuracy without the need for dental implant extraction in patients with head and neck cancer.

Background: The prognosis of advanced squamous cell carcinoma (SCC) of the external auditory canal and middle ear remains poor. Carbon ion radiotherapy (C-ion RT) has shown promise for locally advanced head and neck cancer. Therefore, we evaluated the safety and efficacy of C-ion RT for locally advanced SCC of the external auditory canal and middle ear., Methods: The cases of 13 patients with advanced (T3 and T4) SCC of the external auditory canal and middle ear who received C-ion RT as the primary treatment were reviewed., Results: The median follow-up for all patients and the 7 surviving patients was 12 and 32 months, respectively. The 1-year and 3-year local control and overall survival (OS) rates were 72% and 54% and 70% and 40%, respectively. Severe temporal bone necrosis was observed in 2 patients., Conclusion: C-ion RT is effective and generally safe for locally advanced SCC of the external auditory canal and middle ear., (© 2015 Wiley Periodicals, Inc.)

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbon ions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages., (Copyright © 2015 by the National Comprehensive Cancer Network.)

Background: Treatment of local relapse in adenoid cystic carcinoma (ACC) following prior radiation remains a challenge: without the possibility of surgical salvage patients face the choice between palliative chemotherapy and re-irradiation. Chemotherapy yields response rates around 30% and application of tumouricidal doses is difficult due to proximity of critical structures. Carbon ion therapy (C12) is a promising method to minimize side-effects and maximize re-treatment dose in this indication. We describe our initial results for re-irradiation in heavily pre-treated ACC patients., Methods: Patients treated with carbon ion therapy between 04/2010 and 05/2013 (N=52pts, median age: 54 a) were retrospectively evaluated regarding toxicity (NCI CTC v.4), tumour response (RECIST) and control rates. 48pts (92.3%) received carbon ions only, 4pts received IMRT plus C12., Results: 4pts were treated following R1-resection, 43pts for inoperable local relapse. Most common tumour sites were paranasal sinus (36.5%), parotid (19.2%), and base of skull (17.3%). Pts received a median dose of 51GyE C12/63Gy BED and cumulative dose of 128Gy BED [67-182Gy] after a median RT-interval of 61months. Median target volume was 93ml [9-618ml]. No higher-grade (>°II) acute reactions were observed, 7pts showed blood-brain-barrier changes (°I/II: 8pts; °III: 2pts), 1 pt corneal ulceration, xerophthalmia 7pts, °IV bleeding 1 pt, tissue necrosis 2pts, otherwise no significant late reactions. Objective response rate (CR/PR) was 56.6%. With a median follow-up of 14months [1-39months] local control and distant control at 1a are 70.3% and 72.6% respectively. Of the 18pts with local relapse, 13pts have recurred in-field, 1 pt at the field edge, 3pts out of field, and one in the dose gradient., Conclusion: Despite high applied doses, C12 re-irradiation shows moderate side-effects, response rates even in these heavily pre-treated patients are encouraging and present a good alternative to palliative chemotherapy. Though most local recurrences occur within the high-dose area, further dose escalation should be viewed with caution., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background and Purpose: The aim of this study was to retrospectively analyse the outcomes of cases of adenoid cystic carcinomas (ACCs) of the head and neck that were treated at a single institution with particle therapy consisting of either protons or carbon ions., Methods and Materials: Between February 2002 and March 2012, 80 patients were treated with proton therapy (PT) or carbon ion therapy (CIT) alone. PT and CIT were employed in 40 (50%) patients each, and more than half of the patients received 65.0 GyE in 26 fractions (n=47, 59%)., Results: The median duration of follow-up was 38 months (range, 6-115 months). For all patients, the 5-year for overall survival (OS) rate, progression-free survival (PFS) rate, and local control (LC) rate were 63%, 39%, and 75%, respectively. No significant differences between PT and CIT were observed. The 5-year LC rates for T4 and inoperable cases were 66% and 68%, respectively. Twenty-one patients (26%) experienced grade 3 or greater late toxicities, including three patients who developed grade 5 bleeding from nasopharyngeal ulcers., Conclusions: Particle radiotherapy for ACC achieves favourable LC, and its efficacy in inoperable or T4 cases is promising. There were no significant differences between PT and CIT in terms of OS, PFS and LC., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We introduce the automation of the range difference calculation deduced from particle-irradiation induced β(+)-activity distributions with the so-called most-likely-shift approach, and evaluate its reliability via the monitoring of algorithm- and patient-specific uncertainty factors. The calculation of the range deviation is based on the minimization of the absolute profile differences in the distal part of two activity depth profiles shifted against each other. Depending on the workflow of positron emission tomography (PET)-based range verification, the two profiles under evaluation can correspond to measured and simulated distributions, or only measured data from different treatment sessions. In comparison to previous work, the proposed approach includes an automated identification of the distal region of interest for each pair of PET depth profiles and under consideration of the planned dose distribution, resulting in the optimal shift distance. Moreover, it introduces an estimate of uncertainty associated to the identified shift, which is then used as weighting factor to 'red flag' problematic large range differences. Furthermore, additional patient-specific uncertainty factors are calculated using available computed tomography (CT) data to support the range analysis. The performance of the new method for in-vivo treatment verification in the clinical routine is investigated with in-room PET images for proton therapy as well as with offline PET images for proton and carbon ion therapy. The comparison between measured PET activity distributions and predictions obtained by Monte Carlo simulations or measurements from previous treatment fractions is performed. For this purpose, a total of 15 patient datasets were analyzed, which were acquired at Massachusetts General Hospital and Heidelberg Ion-Beam Therapy Center with in-room PET and offline PET/CT scanners, respectively. Calculated range differences between the compared activity distributions are reported in a 2D map in beam-eye-view. In comparison to previously proposed approaches, the new most-likely-shift method shows more robust results for assessing in-vivo the range from strongly varying PET distributions caused by differing patient geometry, ion beam species, beam delivery techniques, PET imaging concepts and counting statistics. The additional visualization of the uncertainties and the dedicated weighting strategy contribute to the understanding of the reliability of observed range differences and the complexity in the prediction of activity distributions. The proposed method promises to offer a feasible technique for clinical routine of PET-based range verification.

Background: Osteoradionecrosis (ORN) is a critical complication after carbon ion (C-ion) or photon radiotherapy (RT) for head and neck tumors. However, the risk factors for ORN after C-ion RT remain unclear. Therefore, the present study aimed to investigate the effects of the dose-volume relationship on and risk factors for ORN development after C-ion RT. We, however, focused on the maxillary bone because most tumors treated with C-ion RT were primarily located in the sinonasal cavity., Methods: The patients enrolled in this study received more than 10% of the prescribed total dose of 57.6 Gy equivalent (GyE) in 16 fractions to their maxilla. All patients were followed up for more than 2 years after C-ion RT. Those with tumor invasion to the maxilla before C-ion RT or local recurrence after the treatment were excluded from the study to accurately evaluate the effects of irradiation on the bone. Sixty-three patients were finally selected. The severity of ORN was assessed according to the Common Terminology Criteria for Adverse Events version 4.0. The correlation between clinical and dosimetric parameters and ORN incidence was retrospectively analyzed., Results: The median follow-up period was 79 months. Of the 63 enrolled patients, 26 developed ORN of grade ≥1. Multivariate analysis revealed that the maxilla volume receiving more than 50 GyE (V50) and the presence of teeth within the planning target volume were significant risk factors for ORN. Dose-volume histogram analysis revealed that V10 to V50 parameters were significantly higher in patients with ORN than in those without ORN., Conclusions: V50 and the presence of teeth within the planning target volume were independent risk factors for the development of ORN after C-ion RT using a 16-fraction protocol.

Purpose: Particle Therapy Positron Emission Tomography (PT-PET) is a suitable method for verification of therapeutic dose delivery by measurements of irradiation-induced β(+)-activity. Due to metabolic processes in living tissue β(+)-emitters can be removed from the place of generation. This washout is a limiting factor for image quality. The purpose of this study is to investigate whether a washout model obtained by animal experiments is applicable to patient data., Methods: A model for the washout has been developed by Mizuno et al. [Phys. Med. Biol. 48(15), 2269-2281 (2003)] and Tomitani et al. [Phys. Med. Biol. 48(7), 875-889 (2003)]. It is based upon measurements in a rabbit in living and dead conditions. This model was modified and applied to PET data acquired during the experimental therapy project at GSI Helmholtzzentrum für Schwerionenforschung Darmstadt, Germany. Three components are expected: A fast one with a half life of 2 s, a medium one in the range of 2-3 min, and a slow component of the order of 2-3 h. Ten patients were selected randomly for investigation of the fast component. To analyze the other two components, 12 one-of-a-kind measurements from a single volunteer patient are available., Results: A fast washout on the time scale of a few seconds was not observed in the patient data. The medium processes showed a mean half life of 155.7 ± 4.6 s. This is in the expected range. Fractions of the activity not influenced by the washout were found., Conclusions: On the time scale of an in-beam or in-room measurement only the medium-time washout processes play a remarkable role. A slow component may be neglected if the measurements do not exceed 20 min after the end of the irradiation. The fast component is not observed due to the low relative blood filled volume in the brain.