Prognostic analysis of radiation-induced liver damage following carbon-ion radiotherapy for hepatocellular carcinoma.

BACKGROUND: Radiation-induced liver damage (RILD) occasionally occurs following carbon-ion radiotherapy (CIRT) for liver tumors, such as hepatocellular carcinoma (HCC), in patients with impaired liver function disease. However, the associated risk factors remain unknown. The present study aimed to determine the risk factors of RILD after CIRT. METHODS: We retrospectively analyzed 108 patients with HCC treated with CIRT at the Osaka Heavy Ion Therapy Center between December 2018 and December 2022. RILD was defined as a worsening of two or more points in the Child-Pugh score within 12 months following CIRT. The median age of the patients was 76 years (range 47-95 years), and the median tumor diameter was 41 mm (range 5-160 mm). Based on the pretreatment liver function, 98 and 10 patients were categorized as Child-Pugh class A and B, respectively. We analyzed patients who received a radiation dose of 60 Gy (relative biological effectiveness [RBE]) in four fractions. The median follow-up period was 9.7 months (range 2.3-41.1 months), and RILD was observed in 11 patients (10.1%). RESULTS: Multivariate analysis showed that pretreatment Child-Pugh score B (p = 0.003, hazard ratio [HR] = 6.90) and normal liver volume spared from < 30 Gy RBE (VS30 < 739 cm3) (p = 0.009, HR = 5.22) were significant risk factors for RILD. The one-year cumulative incidences of RILD stratified by Child-Pugh class A or B and VS30 < 739 cm3 or ≥ 739 cm3 were 10.3% or 51.8% and 39.6% or 9.2%, respectively. CONCLUSION: In conclusion, the pretreatment Child-Pugh score and VS30 of the liver are significant risk factors for RILD following CIRT for HCC.

Validation of robust radiobiological optimization algorithms based on the mixed beam model for intensity-modulated carbon-ion therapy.

Currently, treatment planning systems (TPSs) that can compute the intensities of intensity-modulated carbon-ion therapy (IMCT) using scanned carbon-ion beams are limited. In the present study, the computational efficacy of the newly designed IMCT algorithms was analyzed for the first time based on the mixed beam model with respect to the physical and biological doses; moreover, the validity and effectiveness of the robust radiobiological optimization were verified. A dose calculation engine was independently generated to validate a clinical dose determined in the TPS. A biological assay was performed using the HSGc-C5 cell line to validate the calculated surviving fraction (SF). Both spot control (SC) and voxel-wise worst-case scenario (WC) algorithms were employed for robust radiobiological optimization followed by their application in a Radiation Therapy Oncology Group benchmark phantom under homogeneous and heterogeneous conditions and a clinical case for range and position errors. Importantly, for the first time, both SC and WC algorithms were implemented in the integrated TPS platform that can compute the intensities of IMCT using scanned carbon-ion beams for robust radiobiological optimization. For assessing the robustness, the difference between the maximum and minimum values of a dose-volume histogram index in the examined error scenarios was considered as a robustness index. The relative biological effectiveness (RBE) determined by the independent dose calculation engine exhibited a -0.6% difference compared with the RBE defined by the TPS at the isocenter, whereas the measured and the calculated SF were similar. Regardless of the objects, compared with the conventional IMCT, the robust radiobiological optimization enhanced the sensitivity of the examined error scenarios by up to 19% for the robustness index. The computational efficacy of the novel IMCT algorithms was verified according to the mixed beam model with respect to the physical and biological doses. The robust radiobiological optimizations lowered the impact of range and position uncertainties considerably in the examined scenarios. The robustness of the WC algorithm was more enhanced compared with that of the SC algorithm. Nevertheless, the SC algorithm can be used as an alternative to the WC IMCT algorithm with respect to the computational cost.

Water extract of Vitis coignetiae Pulliat leaves attenuates oxidative stress and inflammation in progressive NASH rats.

This study aimed to investigate the therapeutic effects of the water extract of leaves of Vitis coignetiae Pulliat (VCPL) on nonalcoholic steatohepatitis (NASH) with advanced fibrosis, as our previous study exhibited its preventive effect on NASH. The NASH animal model [PCT/JP2007/52477] was prepared by loading recurrent and intermittent hypoxemia stress to a rat with fatty liver, which resembled the condition occurring in patients with obstructive sleep apnea (OSA) and fatty liver, who have a high incidence of NASH. Intermittent hypoxemia stress is regarded as a condition similar to warm ischemia followed by re-oxygenation, which induces oxidative stress (OS). The daily 100 or 300 mg/kg VCPL administrations were performed for 3 weeks perorally beginning at the time of detection of advanced liver fibrosis. The therapeutic efficacy of VCPL on NASH was demonstrated by the reduction of the leakage of hepato-biliary enzymes and the amelioration of liver fibrosis. The OS elevation in NASH rats was measured based on the derivation of reactive oxygen species from liver mitochondrial energy metabolism and on the decrease in plasma SOD-like activity. The aggravation of inflammatory responses was demonstrated by the neutrophil infiltration (elevated myeloperoxidase activity) and the progression of fibrosis in the livers of NASH rats. In addition, the NASH rats without VCPL treatment also exhibited activation of nuclear factor-κB, a key factor in the link between oxidative stress and inflammation. All of these changes were reduced dose-dependently by the VCPL administration. These findings indicate that VCPL may improve hepatic fibrosis or at least suppress the progression of NASH, by breaking the crosstalk between OS and inflammation.

Brainstem NTCP and Dose Constraints for Carbon Ion RT-Application and Translation From Japanese to European RBE-Weighted Dose.

BACKGROUND AND PURPOSE: The Italian National Center of Oncological Hadrontherapy (CNAO) has applied dose constraints for carbon ion RT (CIRT) as defined by Japan's National Institute of Radiological Sciences (NIRS). However, these institutions use different models to predict the relative biological effectiveness (RBE). CNAO applies the Local Effect Model I (LEM I), which in most clinical situations predicts higher RBE than NIRS's Microdosimetric Kinetic Model (MKM). Equal constraints therefore become more restrictive at CNAO. Tolerance doses for the brainstem have not been validated for LEM I-weighted dose (D LEM I). However, brainstem constraints and a Normal Tissue Complication Probability (NTCP) model were recently reported for MKM-weighted dose (D MKM), showing that a constraint relaxation to D MKM|0.7 cm3 <30 Gy (RBE) and D MKM|0.1 cm3 <40 Gy (RBE) was feasible. The aim of this work was to evaluate the brainstem NTCP associated with CNAO's current clinical practice and to propose new brainstem constraints for LEM I-optimized CIRT at CNAO. MATERIAL AND METHODS: We reproduced the absorbed dose of 30 representative patient treatment plans from CNAO. Subsequently, we calculated both D LEM I and D MKM, and the relationship between D MKM and D LEM I for various brainstem dose metrics was analyzed. Furthermore, the NTCP model developed for D MKM was applied to estimate the NTCPs of the delivered plans. RESULTS: The translation of CNAO treatment plans to D MKM confirmed that the former CNAO constraints were conservative compared with D MKM constraints. Estimated NTCPs were 0% for all but one case, in which the NTCP was 2%. The relationship D MKM/D LEM I could be described by a quadratic regression model which revealed that the validated D MKM constraints corresponded to D LEM I|0.7 cm3 <41 Gy (RBE) (95% CI, 38-44 Gy (RBE)) and D LEM I|0.1 cm3 <49 Gy (RBE) (95% CI, 46-52 Gy (RBE)). CONCLUSION: Our study demonstrates that RBE-weighted dose translation is of crucial importance in order to exchange experience and thus harmonize CIRT treatments globally. To mitigate uncertainties involved, we propose to use the lower bound of the 95% CI of the translation estimates, i.e., D LEM I|0.7 cm3 <38 Gy (RBE) and D LEM I|0.1 cm3 <46 Gy (RBE) as brainstem dose constraints for 16 fraction CIRT treatments optimized with LEM I.

Skull base chordomas: efficacy of surgery followed by carbon ion radiotherapy.

BACKGROUND: Skull base chordomas are challenging to treat because of their invasive nature, critical location, and aggressive recurrence. We report the effectiveness of combined radical skull base surgery with carbon ion radiotherapy for treating skull base chordomas. METHODS: Between November 1996 and August 2007, 32 patients (12 males and 20 females; mean age at initial presentation 41.4 years, range, 10-75 years) with skull base chordomas underwent 59 operations. Sub-total resection (resection of >90% of the pre-operative tumour volume) was achieved in 24 out of 59 (40.7%) operations. After surgical excision, 9/32 (28.1%) patients underwent adjuvant carbon ion radiotherapy. The patients were followed up for a mean period of 36.3 months (range, 3-93 months) from the initial presentation. FINDINGS: Fifty percent of the patients had to be re-treated due to tumour regrowth during the follow-up period. Thus far, 3 patients have died from the neoplasms. The overall 7 year survival rate of 9 patients who underwent carbon ion radiotherapy was 85.7%. The rate was higher compared to that of others (76.4%). The 3 year recurrence free survival rates of carbon ion therapy treated group was 70.0%, being higher than that of the other groups treated with radiotherapy or untreated (57.1%, and 7.1% respectively). Log-rank analysis showed a significant difference in the recurrence free survival rates between the group treated with adjunctive carbon ion radiotherapy and the untreated group (P = 0.001146). CONCLUSIONS: Surgical removal of the tumour around the brainstem and the optic nerve combined with post-operative carbon ion radiotherapy will improve the survival rate and quality of life of patients with complicated skull base chordomas.

Beneficial effects of Vitis coignetiae Pulliat leaves on nonalcoholic steatohepatitis in a rat model.

Vitis coignetiae Pulliat (Yamabudo) is used as a health juice and wine based on the abundant polyphenols and anthocyanins in its fruit. However, it is not known whether the leaves of this plant confer similar benefits. This study investigated the hepatoprotective effects of aqueous extracts from Vitis coignetiae Pulliat leaves (VCPL) in an animal model of nonalcoholic steatohepatitis (NASH). Rats were fed a choline-deficient high-fat diet for four weeks to generate fatty livers. NASH was induced by oxidative stress loading. Ten weeks later, blood and liver samples were collected from anesthetized animals and assessed biochemically, histologically, and histochemically to determine the extent of oxidative stress injury and the overall effects of VCPL. Six-week VCPL extract supplementation reduced serum levels of liver enzymes, decreased CYP2E1 induction, increased plasma antioxidant activities and delayed the progression of liver fibrosis. The findings suggested that VCPL has strong radical-scavenging activity and may be beneficial in preventing NASH progression.

RBE-weighted dose in carbon ion therapy for ACC patients: Impact of the RBE model translation on treatment outcomes.

PURPOSE/OBJECTIVE: The purpose of this study is to assess the impact of the conversion scheme for relative biological effectiveness (RBE)-weighted dose (DRBE), implemented at our center, on treatment outcomes of adenoid cystic carcinoma (ACC) patients. MATERIAL/METHODS: Treatment plans of 78 ACC patients, optimized with the Local Effect Model (LEM), were recalculated with the modified Microdosimetric Kinetic Model (mMKM). DRBE to 95%, 50% and 2% (DV%) of the clinical target volume (CTV), were selected as relevant parameters to compare LEM and mMKM DRBE. The pattern of failure of ACC treatments was analyzed in relation to uncertainties involved in the DRBE translation methodology. RESULTS: mMKM recalculations of LEM plans, optimized to a prescription dose of 68.8 Gy(RBE), showed a D50% 8% higher, on average, than the expected value (60.8 Gy(RBE)), closer to the most frequently used mMKM prescription DRBE (64 Gy(RBE)). D95% and D2% deviations, with respect to the optimization goals in the two RBE systems, increased of 0.5% and 14.2%, respectively, due to the steeper mMKM RBE variation along the beam path. Local recurrences were mainly (63%) reported in areas where CTV coverage was not satisfactory in the original LEM plan and the mMKM analysis showed that OARs constraints were too conservative. CONCLUSION: No case of local recurrence could be explained by inadequate mMKM target coverage that was not already present in the LEM plan. New constraints have been defined for optic pathways and brainstem to improve target coverage with no expected increase in tissue complications.

Optic nerve constraints for carbon ion RT at CNAO - Reporting and relating outcome to European and Japanese RBE.

BACKGROUND AND PURPOSE: Until now, carbon ion RT (CIRT) dose constraints for the optic nerve (ON) have only been validated and reported in the NIRS RBE-weighted dose (DNIRS). The aim of this work is to improve CNAO's RBE-weighted dose (DLEM) constraints by analyzing institutional toxicity data and by relating it to DNIRS. MATERIAL AND METHODS: A total of 65 ONs from 38 patients treated with CIRT to the head and neck region in the period 2013-14 were analyzed. The absorbed dose (DAbs) of the treatment plans was reproduced and subsequently both DLEM and DNIRS were applied, thus relating CNAO clinical toxicity to DNIRS. RESULTS: Median FU was 47 (26-67) months. Visual acuity was preserved for the 56 ONs in which the old constraints were respected. Three ONs developed visual decline at DLEM|1% ≥71 Gy(RBE)/DLEM|20% ≥68 Gy(RBE), corresponding to DNIRS|1% ≥68 Gy(RBE)/DNIRS|20% ≥62 Gy(RBE). Dose recalculation revealed that NIRS constraints of DNIRS|1% ≤40 Gy(RBE)/DNIRS|20% ≤28 Gy(RBE) corresponded to DLEM|1% ≤50 Gy(RBE)/DLEM|20% ≤40 Gy(RBE). Reoptimization of treatment plans with these new DLEM constraints showed that the dose distribution still complied with NIRS constraints when evaluated in DNIRS. However, due to uncertainties in the method, and to comply with the EQD2-based constraints used at GSI/HIT, a more moderate constraint relaxation to DLEM|1% ≤45 Gy(RBE)/DLEM|20% ≤37 Gy(RBE) has been implemented in CNAO clinical routine since October 2018. CONCLUSION: New DLEM constraints for the ON were derived by analyzing CNAO toxicity data and by linking our results to the experience of NIRS and GSI/HIT. This work demonstrates the value of recalculating and reporting results in both DLEM and DNIRS.

l-[METHYL-(11)C] methionine positron emission tomography for target delineation in malignant gliomas: impact on results of carbon ion radiotherapy.

PURPOSE: To assess the importance of (11)C-methionine (MET)-positron emission tomography (PET) for clinical target volume (CTV) delineation. METHODS AND MATERIALS: This retrospective study analyzed 16 patients with malignant glioma (4 patients, anaplastic astrocytoma; 12 patients, glioblastoma multiforme) treated with surgery and carbon ion radiotherapy from April 2002 to Nov 2005. The MET-PET target volume was compared with gross tumor volume and CTV, defined by using computed tomography/magnetic resonance imaging (MRI). Correlations with treatment results were evaluated between positive and negative extended volumes (EVs) of the MET-PET target for CTV. RESULTS: Mean volumes of the MET-PET targets, CTV1 (defined by means of high-intensity volume on T2-weighted MRI), and CTV2 (defined by means of contrast-enhancement volume on T1-weighted MRI) were 6.35, 264.7, and 117.7 cm(3), respectively. Mean EVs of MET-PET targets for CTV1 and CTV2 were 0.6 and 2.2 cm(3), respectively. The MET-PET target volumes were included in CTV1 and CTV2 in 13 (81.3%) and 11 patients (68.8%), respectively. Patients with a negative EV for CTV1 had significantly greater survival rate (p = 0.0069), regional control (p = 0.0047), and distant control time (p = 0.0267) than those with a positive EV. Distant control time also was better in patients with a negative EV for CTV2 than those with a positive EV (p = 0.0401). CONCLUSIONS: For patients with malignant gliomas, MET-PET has a possibility to be a predictor of outcome in carbon ion radiotherapy. Direct use of MET-PET fused to planning computed tomography will be useful and yield favorable results for the therapy.

Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy.

PURPOSE: To report the results of a Phase I/II clinical trial for patients with malignant gliomas, treated with combined X-ray radiotherapy (XRT), chemotherapy, and carbon ion radiotherapy (CRT). METHODS AND MATERIALS: Between October 1994 and February 2002, 48 patients with histologically confirmed malignant gliomas (16 anaplastic astrocytoma (AA) and 32 glioblastoma multiforme (GBM) were enrolled in a Phase I/II clinical study. The treatment involved the application of 50 Gy/25 fractions/5 weeks of XRT, followed by CRT at 8 fractions/2 weeks. Nimustine hydrochloride (ACNU) were administered at a dose of 100 mg/m(2) concurrently in weeks 1, 4, or 5 of XRT. The carbon ion dose was increased from 16.8 to 24.8 Gray equivalent (GyE) in 10% incremental steps (16.8, 18.4, 20.0, 22.4, and 24.8 GyE, respectively). RESULTS: There was no Grade 3 or higher acute reaction in the brain. The late reactions included four cases of Grade 2 brain morbidity and four cases of Grade 2 brain reaction among 48 cases. The median survival time (MST) of AA patients was 35 months and that of GBM patients 17 months (p = 0.0035). The median progression-free survival and MST of GBM showed 4 and 7 months for the low-dose group, 7 and 19 months for the middle-dose group, and 14 and 26 months for the high-dose group. CONCLUSION: The results of combined therapy using XRT, ACNU chemotherapy, and CRT showed the potential efficacy of CRT for malignant gliomas in terms of the improved survival rate in those patients who received higher carbon doses.

Long-term outcomes after carbon-ion radiotherapy for oral mucosal malignant melanoma.

Oral mucosal malignant melanoma (OMM) is extremely rare and has a poor prognosis. Owing to its rarity, it has not yet been possible to establish an optimal treatment modality. The objective of this study was to evaluate the long-term efficacy of carbon-ion radiotherapy (C-ion RT) for OMM. Between 1997 and 2013, 19 patients with OMM were treated with C-ion RT alone. Patient ages ranged from 44 to 84 years (median, 69 years). Nine men and 10 women were included. OMMs were restaged in accordance with the seventh edition of the tumour/node/metastasis (TNM) Staging System of the International Union Against Cancer. Before treatment, 14 patients had T3 disease and 5 had T4a disease. Three patients were classified as having N1 disease. All patients were classified as having M0. The hard palate was the most frequently involved oral subsite. All patients were treated with 57.6 Gy (relative biological effectiveness) in 16 fractions. The median follow-up period was 61 months (range, 8-190 months). The 5-year local control, overall survival and progression-free survival rates were 89.5%, 57.4% and 51.6%, respectively. For local control and overall survival, T classification was found to be a significant prognostic factor. Grade 2 and 3 osteoradionecrosis was observed in three and four patients, respectively. The presence of teeth within the planning target volume was a significant risk factor for developing osteoradionecrosis. C-ion RT was an effective treatment option with acceptable toxicity for OMM.

Prognostic factors of adenoid cystic carcinoma of the head and neck in carbon-ion radiotherapy: The impact of histological subtypes.

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.

Definitive carbon-ion radiotherapy for locally advanced parotid gland carcinomas.

BACKGROUND: The purpose of this study was to present our evaluation of the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for locally advanced parotid gland carcinomas. METHODS: Clinicopathological features and outcomes were evaluated in 46 patients receiving C-ion RT for parotid gland carcinomas. RESULTS: Sixteen patients had adenoid cystic carcinoma; 8 had adenocarcinoma, 8 had mucoepidermoid carcinoma, and 14 had other carcinomas. T2, T3, T4a, and T4b diseases were diagnosed in 3, 18, 8, and 17 patients, respectively. C-ion RT was provided to 25 patients as the primary treatment, to 20 patients for local recurrences after surgery, and to 1 patient for residual tumor after surgery. During follow-up (median duration, 62 months), 5-year local control and overall survival (OS) rates were 74.5% and 70.1%, respectively. Of the 30 patients without facial nerve palsy before C-ion RT, 25 showed no radiation-induced facial nerve palsy. CONCLUSION: C-ion RT is effective and has acceptable toxicity levels for locally advanced parotid gland carcinomas. © 2016 Wiley Periodicals, Inc. Head Neck 39: 724-729, 2017.

Physicists' views on hadrontherapy: a survey of members of the Italian Association of Medical Physics (AIFM).

BACKGROUND: This study was based on a survey to investigate perceptions of hadrontherapy of the members of the Italian Association of Medical Physics (AIFM). The survey was digitally submitted to the 991 members between the end of January and the beginning of April 2016. METHODS: A 19-item questionnaire was designed focusing on advantages and disadvantages of hadrontherapy, current status and possible future improvements, and need and opportunities for future investments in Italy and abroad. Information about professional qualifications, main fields of clinical involvement and specific competencies of the respondents was also collected. RESULTS: The survey was completed by 121 AIFM members (response rate 12.2%). In the answers collected, it was shown that medical physicists expressed interest in hadrontherapy mainly for reasons of personal interest rather than for professional needs (90% ± 2.5% vs. 52% ± 4.3% of the respondents, respectively), with a good knowledge of the related basic aspects as well as of the pros and cons of its application. However, poor knowledge of the current status of hadrontherapy was observed among the medical physicists not directly involved at a professional level, who were less than 3% of the physicists working in radiotherapy. CONCLUSIONS: In light of these results, the implementation of new training and education initiatives should be devised to promote a deeper and global knowledge of hadrontherapy-related issues, not only from a theoretical point of view but also in practical terms. Moreover, a close collaboration between highly specialized medical physicists employed in hadrontherapy centers and others in oncology hospitals should be -encouraged.

Phase II multi-institutional clinical trial on a new mixed beam RT scheme of IMRT on pelvis combined with a carbon ion boost for high-risk prostate cancer patients.

PURPOSE: Definition of the optimal treatment schedule for high-risk prostate cancer is under debate. A combination of photon intensity modulated radiotherapy (IMRT) on pelvis with a carbon ion boost might be the optimal treatment scheme to escalate the dose on prostate and deliver curative dose with respect to normal tissue and quality of dose distributions. In fact, carbon ion beams offer the advantage to deliver hypofractionated radiotherapy (RT) using a significantly smaller number of fractions compared to conventional RT without increasing risks of late effects. METHODS: This study is a prospective phase II clinical trial exploring safety and feasibility of a mixed beam scheme of carbon ion prostate boost followed by photon IMRT on pelvis. The study is designed to enroll 65 patients with localized high-risk prostate cancer at 3 different oncologic hospitals: Istituto Europeo di Oncologia, Fondazione IRCCS Istituto Nazionale dei Tumori, and Centro Nazionale di Adroterapia Oncologica. The primary endpoint is the evaluation of safety and feasibility with acute toxicity scored up to 1 month after the end of RT. Secondary endpoints are treatment early (3 months after the end of RT) and long-term tolerability, quality of life, and efficacy. RESULTS: The study is not yet recruiting; in silico studies are ongoing and we expect to start recruitment by 2017. CONCLUSIONS: The present clinical trial aims at improving the current treatment for high-risk prostate cancer, evaluating safety and feasibility of a new RT mixed-beam scheme including photons and carbon ions. Encouraging results are coming from carbon ion facilities worldwide on the treatment of different tumors including prostate cancers. Carbon ions combine physical properties allowing for high dose conformity and advantageous radiobiological characteristics. The proposed mixed beam treatment has the advantage to combine a photon high conformity standard of care IMRT phase with a hypofractionated carbon ion RT boost delivered in a short overall treatment time.

Outcomes of visual acuity in carbon ion radiotherapy: analysis of dose-volume histograms and prognostic factors.

PURPOSE: To analyze the tolerance dose for retention of visual acuity in patients with head-and-neck tumors treated with carbon ion radiotherapy. METHODS AND MATERIALS: From June 1994 to March 2000, 163 patients with tumors in the head and neck or skull base region were treated with carbon ion radiotherapy. Analysis was performed on 54 optic nerves (ONs) corresponding to 30 patients whose ONs had been included in the irradiated volume. These patients showed no evidence of visual impairment due to other factors and had a follow-up period of >4 years. All patients had been informed of the possibility of visual impairment before treatment. We evaluated the dose-complication probability and the prognostic factors for the retention of visual acuity in carbon ion radiotherapy, using dose-volume histograms and multivariate analysis. RESULTS: The median age of 30 patients (14 men, 16 women) was 57.2 years. Median prescribed total dose was 56.0 gray equivalents (GyE) at 3.0-4.0 GyE per fraction per day (range, 48-64 GyE; 16-18 fractions; 4-6 weeks). Of 54 ONs that were analyzed, 35 had been irradiated with <57 GyE (maximum dose [Dmax]) resulting in no visual loss. Conversely, 11 of the 19 ONs (58%) irradiated with >57 GyE (Dmax) suffered a decrease of visual acuity. In all of these cases, the ONs had been involved in the tumor before carbon ion radiotherapy. In the multivariate analysis, a dose of 20% of the volume of the ON (D20) was significantly associated with visual loss. CONCLUSIONS: The occurrence of visual loss seems to be correlated with a delivery of >60 GyE to 20% of the volume of the ON.

Single-energy metal artefact reduction with CT for carbon-ion radiation therapy treatment planning.

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.

Radiation-induced Parotid Gland Atrophy in Patients with Head and Neck Cancer After Carbon-ion Radiotherapy.

BACKGROUND/AIM: This study aimed to clarify the relationship between dosimetric factors and parotid gland (PG) atrophy after carbon ion radiotherapy (C-ion RT). PATIENTS AND METHODS: Fifty-four patients with head and neck tumours were enrolled and 93 irradiated PGs were analyzed. Thirty and 24 patients were treated with total doses [relative biological effectiveness (RBE)] of 57.6 Gy and 64.0 Gy, respectively, in 16 fractions. PG volumes were measured using computed tomographic images obtained before C-ion RT and every 3-6 months thereafter. RESULTS: The median follow-up period was 46.4 months (range=24.0-123.0 months). Univariate analysis showed that PG volumes receiving more than 5, 10, 15, and 20 Gy RBE (V5, V10, V15 and V20, respectively), mean dose, and maximum dose were significantly associated with PG atrophy. Multivariate analysis indicated that only V5 was significantly associated with atrophy. CONCLUSION: Increasing V5 was a significant risk factor for PG atrophy after C-ion RT.

Evaluation of the safety and efficacy of carbon ion radiotherapy for locally advanced adenoid cystic carcinoma of the tongue base.

BACKGROUND: Most cases of adenoid cystic carcinoma (ACC) of the tongue base are radioresistant, and are diagnosed in the advanced stage. Therefore, we evaluated the safety and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced ACC of the tongue base. METHODS: Eighteen patients with ACC of the tongue base were treated with C-ion RT between May 2002 and April 2014. Seventeen patients had T4a disease and 1 patient had T2 disease before C-ion RT. RESULTS: The median follow-up period was 57 months (range, 10-132 months). The 5-year local control rate was 92%. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 72% and 44%, respectively. Regarding late reactions, 2 patients developed grade 3 mandible osteoradionecrosis, and 1 had grade 3 hemorrhage of the tongue base. CONCLUSION: C-ion RT was effective with acceptable toxicities for locally advanced ACC of the tongue base. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2122-E2126, 2016.

Carbon ion radiotherapy for locally advanced squamous cell carcinoma of the external auditory canal and middle ear.

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.