Impact of dose volume parameters and clinical characteristics on radiation-induced acute oral mucositis for head and neck cancer patients treated with carbon-ion radiotherapy dose volume outcome analysis.

OBJECTIVES: To assess the predictive value of different dosimetric parameters for acute radiation oral mucositis (ROM) in head and neck cancer (HNCs) patients treated with carbon-ion radiotherapy (CIRT). METHODS: 44 patients with HNCs treated with CIRT were evaluated for acute ROM which was defined as severe when the score ≥3 (acute ROM was scored prospectively using the Radiation Therapy Oncology Group (RTOG) score system). Predictive dosimetric factors were identified by using univariate and multivariate analysis. RESULTS: Male gender, weight loss >5%, and total dose/fractions were related factors to severe ROM. In multivariate analysis, grade ≥3 ROM was significantly related to the Dmax, D10, D15, and D20 (P < 0.05, respectively). As the receiver operating characteristics (ROC) curve shows, the area under the curve (AUC) for D10 was 0.77 (p = 0.003), and the cutoff value was 51.06 Gy (RBE); The AUC for D15 was 0.75 (p = 0.006), and the cutoff value was 42.82 Gy (RBE); The AUC for D20 was 0.74 (p = 0.009), and the cutoff value was 30.45 Gy (RBE); The AUC for Dmax was 0.81 (p < 0.001), and the cutoff value was 69.33 Gy (RBE). CONCLUSION: Male gender, weight loss, and total dose/fractions were significantly association with ROM. Dmax, D10, D15 and D20 were identified as the most valuable predictor and we suggest a Dmax limit of 69.33 Gy (RBE), D10 limit of 51.06 Gy (RBE), D15 limit of 42.82 Gy (RBE), and D20 limit of 30.45 Gy (RBE) and for oral mucosa.

The incidence and risk factors for early death among patients with oral tongue squamous cell carcinomas.

BACKGROUND: The objective of this study is to evaluate the early mortality rate and associated factors for early death in oral tongue squamous cell carcinomas (OTSCC) patients. METHODS: Patients with OTSCC were extracted from the SEER database between 2004 and 2014. The early death (survival time≤3 months) rate was calculated, and associated risk factors were evaluated by the logistic regression models. RESULTS: A total of 7756 patients were analysed and 282 (3.6%) patients died within 3 months after cancer diagnosis, among whom 214 (2.8%) patients died from cancer-specific cause. In univariate analyses, advanced age, divorced/single/widowed (DSW), higher histological grades, black, advanced T stage, advanced N stage, distant metastasis and no surgery were significantly associated with all-causes and cancer-specific early death. Multivariate analyses showed that advanced age, DSW, advanced T stage, advanced N stage, distant metastasis, and no surgery were significantly associated with all-cause and cancer-specific early death. CONCLUSION: Our results showed that a total of 3.6% patients with OTSCC suffered early death. Predictors of early death are primarily related to age older than 60 years, advanced T stage, advanced N stage, distant metastasis and no surgery but also include unmarried status, but better prognostic and predictive tools in larger sample to select early death patients are needed.

Clinical outcomes of carbon-ion radiotherapy for patients with locoregionally recurrent nasopharyngeal carcinoma.

BACKGROUND: Reirradiation for locoregionally recurrent nasopharyngeal carcinoma (LR-NPC) after high-dose radiotherapy (RT) is challenging and usually is associated with poor survival and severe toxicities. Because of its physical and biological advantages over photon-beam RT, carbon-ion RT (CIRT) could be a potential treatment option for patients with LR-NPC. METHODS: Patients with LR-NPC who underwent salvage therapy using CIRT at the Shanghai Proton and Heavy Ion Center between May 2015 and June 2019 were analyzed. CIRT doses were 50 to 69 gray equivalent (GyE) (2.0-3.0 GyE per fraction). Overall survival (OS), local control, regional control, distant control, and acute and late toxicities were analyzed. Univariable and multivariable analyses of OS and local control were performed using the Cox regression model. RESULTS: Among the 206 patients included, 139 patients (67.5%) had recurrent American Joint Committee on Cancer stage III or stage IV disease. With a median follow-up of 22.8 months, the 2-year OS, local control, regional control, and distant control rates were 83.7%, 58.0%, 87.3%, and 94.7%, respectively. Multivariable analysis revealed that older age (P = .017) was predictive of worse OS, whereas a larger tumor volume (P = .049) and a lower biological equivalent dose (P = .029) were associated with inferior local control. No patient developed an acute toxicity of ≥grade 3 during CIRT. Severe (≥grade 3) late toxicities included temporal lobe necrosis (0.97%), cranial neuropathy (0.49%), hearing loss (1.46%), xerostomia (0.49%), and mucosal necrosis (16.02%) (toxicities were graded using the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer criteria). CONCLUSIONS: Salvage treatment using CIRT is efficacious for patients with LR-NPC and its toxicities are acceptable. CIRT may improve the survival and toxicity profiles substantially for patients with LR-NPC compared with the reported results after photon-based intensity-modulated RT.

Salvage treatment using carbon ion radiation in patients with locoregionally recurrent nasopharyngeal carcinoma: Initial results.

BACKGROUND: Reirradiation for locoregionally recurrent nasopharyngeal carcinoma (NPC) after a definitive dose of radiotherapy (RT) is challenging and usually associated with severe toxicities. Intensity-modulated carbon ion RT (IMCT) offers physical/biologic advantages over photon-based intensity-modulated RT. Herein, the authors report their initial experience of IMCT in previously irradiated patients with locoregionally recurrent NPC. METHODS: Patients with locoregionally recurrent, poorly differentiated or undifferentiated NPC who underwent salvage therapy with IMCT at the Shanghai Proton and Heavy Ion Center between May 2015 and August 2017 were included in the current study. The IMCT doses were 50 to 66 Gray equivalent (GyE) (2.0-3.0 GyE/daily fraction), delivered via raster scanning technology. The 1-year overall survival, disease-specific survival, progression-free survival (PFS), local recurrence-free survival, regional recurrence-free survival, and distant metastasis-free survival were calculated. Univariate and multivariate analyses of PFS were performed to identify possible predictive factors. RESULTS: Among the 75 patients included, 4 patients, 14 patients, 29 patients, and 28 patients, respectively, had recurrent American Joint Committee on Cancer stage I, stage II, stage III, and stage IVA/B disease. With a median follow-up of 15.4 months (range, 2.6-29.7 months), the 1-year overall survival, disease-specific survival, PFS, local recurrence-free survival, regional recurrence-free survival, and distant metastasis-free survival rates were 98.1%, 98.1%, 82.2%, 86.6%, 97.9%, and 96.2%, respectively. A higher fraction size of 3 GyE (vs <3 GyE) or a higher biological equivalent dose significantly improved the PFS rate on univariate analysis, but not on multivariate analysis. No patient developed acute toxicity of grade ≥2 during IMCT. Late treatment-induced severe (grade 3 or 4) toxicities were infrequent, but included mucosal necrosis (9.3%), xerostomia (1.3%), and temporal lobe necrosis (1.3%). CONCLUSIONS: This initial experience in the first 75 patients with locoregionally recurrent NPC was encouraging. Carbon ion RT could provide promising survival rates with infrequent severe toxicities for patients with locoregionally recurrent NPC. Cancer 2018;124:2427-37. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Survival outcomes and toxicity profiles among patients with nonmetastatic nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) versus IMRT + carbon-ion radiotherapy: A propensity score-matched analysis.

OBJECTIVES: To compare survival outcomes and toxic effects among patients with newly diagnosed nonmetastatic nasopharyngeal carcinoma (NPC) when treated with intensity-modulated radiotherapy (IMRT) versus IMRT + carbon-ion radiotherapy (CIRT). METHODS: We performed a retrospective propensity score matching analysis (1:1) of patients treated with IMRT and IMRT + CIRT. Descriptive statistics were used to examine the baseline characteristics of the patients. Survival was estimated using the Kaplan-Meier method. Univariate and multivariable logistic regression analysis were used to identify the independent predictors of survival. We examined the association between risk factors and adverse events (AEs) using chi-square tests. Cox model and logistic regression were used to analyze AEs. RESULTS: Hundred and nine patients who received IMRT + CIRT were included and the median follow-up time was 20.6 months (range: 4.6-82 months). There were no statistically significant differences in locoregional failure-free survival, distant metastasis-free survival, disease-free survival, or overall survival between the two groups, but potentially better in IMRT + CIRT group (p > 0.05, respectively). Nodal boost was the only significant factor associated with LRFS and DFS on multivariable analysis. Thirty-seven patients (34.0%) developed grade 3 acute OMs and no grade 4 acute OMs were observed in IMRT + CIRT group. All patients in IMRT + CIRT group developed grade 1 dermatitis; while in the match group, 76 patients developed grade 1 dermatitis, 27 patients developed grade 2 dermatitis, 5 patients developed grade 3 dermatitis, 1 patient developed grade 4 dermatitis. IMRT + CIRT treatment was associated with a significant trend of lower grades of OM and dermatitis (p < 0.05, respectively). Any severe (i.e., grade 3) chronic AEs, such as xerostomia, skin fibrosis, temporal lobe necrosis, osteoradionecrosis, or radiation-induced optic neuropathy, was not observed. CONCLUSIONS: In this study, IMRT + CIRT was associated with significantly reduced acute toxicity burden compared with full course of IMRT, with excellent survival outcomes. Patients with persistent disease after treatment and treated with nodal boost had a worse outcome. More accurate assessments of IMRT + CIRT to primary nonmetastatic NPC patients will be imperative.

Normal tissue complication probability model of temporal lobe injury following re-irradiation of IMRT for local recurrent nasopharyngeal carcinoma.

Purpose: We tried to establish the normal tissue complication probability (NTCP) model of temporal lobe injury of recurrent nasopharyngeal carcinoma (NPC) patients after two courses of intensity modulated radiotherapy (IMRT) to provide more reliable dose-volume data reference to set the temporal lobe tolerance dose for recurrent NPC patients in the future. Methods and materials: Recurrent NPC patients were randomly divided into training data set and validation data set in a ratio of 2:1, All the temporal lobes (TLs) were re-contoured as R/L structures and named separately in the MIM system. The dose distribution of the initial IMRT plan was deformed into the second course planning CT via MIM software to get the deformed dose. Equivalent dose of TLs in 2Gy fractions was calculated via linear quadratic model, using an α/ß=3 for temporal lobes. NTCP model that correlated the irradiated volume of the temporal lobe and? the clinical variables were evaluated in a multivariate prediction model using AUC analysis. Results: From Jan. 2010 to Dec. 2020, 78 patients were enrolled into our study. Among which 26 (33.3%) developed TLI. The most important factors affecting TLI was the sum-dose d1.5cc of TL, while the possible clinical factors did not reach statistically significant differences in multivariate analysis. According to NTCP model, the TD5 and TD50 EQD2 dose of sum-dose d1.5cc were 65.26Gy (46.72-80.69Gy) and 125.25Gy (89.51-152.18Gy), respectively. For the accumulated EQD2 dose, the area under ROC shadow was 0.8702 (0.7577-0.9828) in model validation, p<0.001. Conclusion: In this study, a NTCP model of temporal lobe injury after a second course of IMRT for recurrent nasopharyngeal carcinoma was established. TD5 and TD50 doses of temporal lobe injury after re-RT were obtained according to the model, and the model was verified by validation set data.

Clinical Implementation of a 6D Treatment Chair for Fixed Ion Beam Lines.

PURPOSE: To verify the practicality and safety of a treatment chair with six degrees of freedom (6DTC) through demonstrating the efficacy of the workflow in clinical settings and analyzing the obtained technical data, including intra-fraction patient movement during the use of the 6DTC. MATERIALS AND METHODS: A clinical study was designed and conducted to test the clinical treatment workflow and the safety of the 6DTC. Based on the demonstrated dosimetric advantages, fifteen patients with head and neck tumors were selected and treated with the 6DTC. The positional error at the first beam position (PE-B1) and the second beam position (PE-B2) were analyzed and compared with the results from daily quality assurance (QA) procedures of the 6DTC and imaging system performed each day before clinical treatment. The intra-fraction patient movement was derived from the total patient alignment positional error and the QA data based on a Gaussian distribution formulism. RESULTS: The QA results showed sub-millimeter mechanical accuracy of the 6DTC over the course of the clinical study. For 150 patient treatment fractions, the mean deviations between PE-B1 and PE-B2 were 0.13mm (SD 0.88mm), 0.25mm (SD 1.17mm), -0.57mm (SD 0.85mm), 0.02° (SD 0.35°), 0.00° (SD 0.37°), and -0.02° (SD 0.37°) in the x, y, z (translational), and u, v, w (rotational) directions, respectively. The calculated intra-fraction patient movement was -0.08mm (SD 0.56mm), 0.71mm (SD 1.12mm), -0.52mm (SD 0.84mm), 0.10° (SD 0.32°), 0.09° (SD 0.36°), and -0.04° (SD 0.36°) in the x, y, z, u, v, w directions, respectively. CONCLUSIONS: The performance stability of the 6DTC was satisfactory. The position accuracy and intra-fraction patient movement in an upright posture with the 6DTC were verified and found adequate for clinical implementation.

Mixed Photon and Carbon-Ion Beam Radiotherapy in the Management of Non-Metastatic Nasopharyngeal Carcinoma.

BACKGROUND: Carbon-ion radiotherapy (CIRT) may further increase the therapeutic ratio for patients with newly diagnosed nasopharyngeal carcinoma (NPC). The purpose of the current study is to examine the effectiveness and toxicity profile of photon-based intensity-modulated radiotherapy (IMRT) plus CIRT boost in a relatively large cohort of NPC patients. METHODS: In the current study, non-metastatic NPC patients treated with IMRT plus CIRT boost at Shanghai Proton and Heavy Ion Center between June, 2015 and June, 2018 were included. Overall survival (OS), progression-free survival (PFS), local control, regional control, and distant control were calculated with Kaplan-Meier method. Acute and late toxicities were graded using CTCAE 4.03. RESULTS: A total of 69 patients were included in the analysis. Among those, 74% of the patients had locoregionally advanced (stage III/IV) disease, and 92.8% had cervical lymphadenopathy. With a median follow-up of 31.9 months, the 3-year OS, PFS, local control, regional control, and distant control rates were 94.9, 85.2, 96.9, 98.4, and 89.7%, respectively. Mixed treatment of IMRT with CIRT boost was well tolerated. Severe acute toxicities induced by radiation therapy were observed in only two patients (dermatitis). No severe radiation-induced late toxicity was observed at the time of analysis. Univariable analysis showed N2/3 disease was correlated with an inferior distant control (p = 0.040). CONCLUSION: Mixed treatment of IMRT plus CIRT boost provides an excellent disease control and a favorable toxicity profile for patients with non-metastatic NPC. Further follow-up is necessary to evaluate the long-term survivals and toxicities more accurately.

Particle Beam Radiation Therapy for Skull Base Sarcomas.

Background: To report the clinical experience of carbon-ion and proton radiation therapy for skull base sarcomas. Methods: An analysis of the retrospective data registry from the Shanghai Proton and Heavy Ion Center for patients with skull base sarcomas was conducted. The 1-/2-year local relapse-free, distant metastasis-free, progression-free, and overall survival (LRFS, DMFS, PFS, OS) rates as well as associated prognostic indicators were analyzed. Radiotherapy-induced acute and late toxicities were summarized. Results: Between 7/2014 and 5/2019, 62 patients with skull base sarcomas of various subtypes received carbon-ion radiation therapy (53), proton radiation therapy (5), or proton radiation therapy + carbon-ion boost (4). With a median follow-up of 20.4 (range 2.73-91.67) months, the 1-/2-year OS, LRFS, DMFS, and PFS rates were 91.2%/80.2%, 89.2%/80.2%, 86.0%/81.1%, and 75.8%/62.9%, respectively. Grade 3 mucositis and grade 4 hemorrhage were observed in 1 patient for each. Only grade 1 and grade 2 toxicities were observed except for the same patient with grade 4 acute toxicity died of severe hemorrhage (grade 5). Multivariate analyses revealed the lack of prior RT was an independent favorable prognostic factor for OS, PFS, and LRFS, age under 40 was associated with improved OS, early T-disease (T1/2) showed a significant association with better PFS. Conclusion: With few observed acute and late toxicities, particle beam radiation therapy provided effective tumor control and overall survival for patients with skull base sarcomas.

The preliminary results of proton and carbon ion therapy for chordoma and chondrosarcoma of the skull base and cervical spine.

PURPOSE: To evaluate the short-term outcomes in terms of tumor control and toxicity of patients with skull base or cervical spine chordoma and chondrosarcoma treated with intensity-modulated proton or carbon-ion radiation therapy. METHODS: Between 6/2014 and 7/2018, a total of 91 patients were treated in our Center. The median age was 38 (range, 4-70) years. Forty-six (50.5%) patients were treated definitively for their conditions as initial diagnosis, 45 (49.5%) patients had recurrent tumors including 14 had prior radiotherapy. The median gross tumor volume was 37.0 (range, 1.6-231.7) cc. Eight patients received proton therapy alone, 28 patients received combined proton and carbon ion therapy, 55 patients received carbon-ion therapy alone. RESULTS: With a median follow-up time of 28 (range, 8-59) months, the 2-year local control (LC), progression free (PFS) and overall survival (OS) rates was 86.2, 76.8, and 87.2%, respectively. Those rates for patients received definitive proton or carbon-ion therapy were 86.7, 82.8, and 93.8%, respectively. On multivariate analyses, tumor volume of > 60 cc was the only significant factor for predicting PFS (p = 0.045), while re-irradiation (p = 0.012) and tumor volume (> vs < 60 cc) (p = 0.005) were significant prognosticators for OS. Grade 1-2 late toxicities were observed in 11 patients, and one patient developed Grade 3 acute mucositis. CONCLUSIONS: Larger tumor volume and re-irradiation were related to inferior survival for this group of patients. Further follow-up is needed for long-term efficacy and safety.

Salvage Carbon-Ion Radiation Therapy For Locoregionally Recurrent Head and Neck Malignancies.

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.

Use of Radiation Therapy in Metastatic Nasopharyngeal Cancer Improves Survival: A SEER Analysis.

Limited data indicated radiotherapy might provide survival benefits to patients with distantly metastatic nasopharyngeal carcinoma (mNPC). We used the Surveillance Epidemiology and End Results database to examine the role of radiotherapy in the treatment of mNPC. Patients with mNPC at presentation diagnosed between 1988 and 2012 were enrolled. The outcome of interest included overall survival (OS) and cancer-specific survival (CSS). A total of 679 patients with a median follow-up of 13 months were identified. Four hundred forty-eight patients received radiotherapy and 231 did not. Radiotherapy was associated with significantly improved OS and CSS in both univariate and multivariate analyses. Weighted Cox regression by inverse probability of treatment weighting (IPTW) using propensity score (PS) showed a 50% reduced risk of mortality in patients who received radiotherapy with regards to both OS (HR: 0.50, 95% CI: 0.41-0.60, p < 0.001) and CSS (HR: 0.50, 95% CI: 0.40-0.61, p < 0.001), respectively. Further, patients with a younger age (<65 year-old), diagnosed after 2003, with non-keratinizing carcinoma or undifferentiated carcinoma, and who received surgery had better outcomes for both OS and CSS. Local radiotherapy was associated with improved survival in patients with mNPC. Our findings warrant prospective investigation in clinical trials.

Phase I/II trial evaluating concurrent carbon-ion radiotherapy plus chemotherapy for salvage treatment of locally recurrent nasopharyngeal carcinoma.

BACKGROUND: After definitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma (NPC), more than 10% of patients will experience a local recurrence. Salvage treatments present significant challenges for locally recurrent NPC. Surgery, stereotactic ablative body radiotherapy, and brachytherapy have been used to treat locally recurrent NPC. However, only patients with small-volume tumors can benefit from these treatments. Re-irradiation with X-ray-based intensity-modulated radiotherapy (IMXT) has been more widely used for salvage treatment of locally recurrent NPC with a large tumor burden, but over-irradiation to the surrounding normal tissues has been shown to cause frequent and severe toxicities. Furthermore, locally recurrent NPC represents a clinical entity that is more radio-resistant than its primary counterpart. Due to the inherent physical advantages of heavy-particle therapy, precise dose delivery to the target volume(s), without exposing the surrounding organs at risk to extra doses, is highly feasible with carbon-ion radiotherapy (CIRT). In addition, CIRT is a high linear energy transfer (LET) radiation and provides an increased relative biological effectiveness compared with photon and proton radiotherapy. Our prior work showed that CIRT alone to 57.5 GyE (gray equivalent), at 2.5 GyE per daily fraction, was well tolerated in patients who were previously treated for NPC with a definitive dose of IMXT. The short-term response rates at 3-6 months were also acceptable. However, no patients were treated with concurrent chemotherapy. Whether the addition of concurrent chemotherapy to CIRT can benefit locally recurrent NPC patients over CIRT alone has never been addressed. It is possible that the benefits of high-LET CIRT may make radiosensitizing chemotherapy unnecessary. We therefore implemented a phase I/II clinical trial to address these questions and present our methodology and results. METHODS AND DESIGN: The maximal tolerated dose (MTD) of re-treatment using raster-scanning CIRT plus concurrent cisplatin will be determined in the phase I, dose-escalating stage of this study. CIRT dose escalation from 52.5 to 65 GyE (2.5 GyE × 21-26 fractions) will be delivered, with the primary endpoints being acute and subacute toxicities. Efficacy in terms of overall survival (OS) and local progression-free survival of patients after concurrent chemotherapy plus CIRT at the determined MTD will then be studied in the phase II stage of the trial. We hypothesize that CIRT plus chemotherapy can improve the 2-year OS rate from the historical 50% to at least 70%. CONCLUSIONS: Re-treatment of locally recurrent NPC using photon radiation techniques, including IMXT, provides moderate efficacy but causes potentially severe toxicities. Improved outcomes in terms of efficacy and toxicity profile are expected with CIRT plus chemotherapy. However, the MTD of CIRT used concurrently with cisplatin-based chemotherapy for locally recurrent NPC remains to be determined. In addition, whether the addition of chemotherapy to CIRT is needed remains unknown. These questions will be evaluated in the dose-escalating phase I and randomized phase II trials.

Phase I/II Trial Evaluating Carbon Ion Radiotherapy for Salvaging Treatment of Locally Recurrent Nasopharyngeal Carcinoma.

BACKGROUND: Radiation therapy is the mainstay strategy for the treatment of nasopharyngeal cancer (NPC). Intensity-modulated X-ray therapy (IMXT) alone is the current standard for stage I and II NPC. For stage III and IV A/B diseases, concurrent chemotherapy should be provided in addition to IMXT. However, optimal treatment for locally recurrent NPC after previous definitive dose of radiotherapy is lacking. Various techniques including brachytherapy, IMXT, stereotactic radiosurgery or radiotherapy (SRS or SBRT) have been used in the management of locally recurrent NPC. Due to the inherent limitation of these techniques, i.e., limited range of irradiation or over-irradiation to surrounding normal tissues, moderate efficacy has been observed at the cost of severe toxicities. Carbon ion radiotherapy (CIRT) offers potential physical and biological advantages over photon and proton radiotherapy. Due to the inverted dose profile of particle beams and their greater energy deposition within the Bragg peak, precise dose delivery to the target volume(s) without exposing the surrounding organs at risk to extra doses is possible. In addition, CIRT provides an increased relative biological effectiveness (RBE) as compared to photon and proton radiotherapy. Such advantages may translate to improved outcomes after irradiation in terms of disease control in radio-resistant and previously treated, recurrent malignancies. It is therefore reasonable to postulate that recurrent NPC after high-dose radiotherapy could be more resistant to re-irradiation using photons. Reports on the treatment of radio-resistant malignancies in the head and neck region such as melanoma, sarcoma, and adenoid cystic carcinoma (ACC) have demonstrated superior local control rates from CIRT as compared to photon irradiation. Thus patients with recurrent NPC are likely to benefit from the enhanced biological effectiveness of carbon ions. As effective retreatment strategy is lacking for locally recurrent NPC, carbon ion radiation therapy offers an ideal alternate to conventional X-ray irradiation. METHODS AND DESIGN: The recommended dose of re-irradiation using CIRT for locally recurrent NPC will be determined in the dose-escalating phase (Phase I) of the study. Efficacy in terms of local progression-free survival (LPFS) and overall survival (OS) will be studied in the second phase of the study. Increasing doses of CIRT using raster scanning technology from 55GyE (22×2.5 GyE) to 65 GyE (26× 2.5 GyE) will be delivered in the Phase I part of the study. The primary endpoint of the Phase I part of the study is acute and sub-acute toxicities; the primary endpoint in the Phase II part is local progression-free survival and overall survival. Using the historical 2-year OS rate of 50% in locally recurrent NPC patients treated with photon or proton, we hypothesize that CIRT can improve the 2-year OS rate to 70%. DISCUSSION: The utilization of conventional radiation techniques including IMXT, brachytherapy, or stereotactic radiation therapy provides moderate efficacy in the treatment of locally recurrent NPC due to the limitations in dose distribution and biological effectiveness. Improved outcome in terms of treatment-induced toxicity, LC, LPFS, and OS are expected using CIRT due to the physical and biological characteristics of carbon ion beam. However, the recommended dose of CIRT used in re-irradiation for the local NPC focus remain to be determined. The recommended dose as well as the efficacy of CIRT in the treatment of locally recurrent NPC will be evaluated in the present trial.

Concurrent chemoradiotherapy comparison of taxanes and platinum versus 5-fluorouracil and platinum in nasopharyngeal carcinoma treatment.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a squamous-cell carcinoma especially prevailing among the natives of southern China. The regimen of concurrent chemoradiotherapy (CCRT) that include platinum and 5-fluorouracil (5-FU) is considered to be the standard treatment for NPC. However, its clinical use is limited by its toxicity. Our purpose was to evaluate the efficacy and safety of the regimen of CCRT with taxanes and platinum versus the regimen of CCRT with 5-FU and platinum in NPC treatment. METHODS: Medline, the Cochrane library, and the Chinese medical literature database were searched for eligible studies. Meta-analysis was performed using Review Manager (Version 5.2). RESULTS: Six random controlled trials (RCTs) including 514 patients met our criteria. Meta-analysis showed that the regimen of CCRT with taxanes and platinum had an improved significant difference in complete remission (CR) and less incidence rate in adverse reactions such as gastrointestinal impairment grades III-IV, liver and kidney impairment grades I-II, and radiodermatitis grades III-IV versus the conventional regimen of CCRT with 5-FU and platinum, while the longterm effectiveness rate of overall survival, locoregional failure-free survival, or distant metastasis failure-free survival between the two groups was therapeutic equivalence. CONCLUSIONS: The regimen of CCRT with taxanes and platinum in NPC therapy may be more efficient and safe compared to the conventional modality of 5-FU and platinum in CCRT. However, we need more high-quality studies of multi-center and randomized double-blind clinical trials to further compare, analyze, and confirm the findings.

Lymph node metastasis in sinonasal squamous cell carcinoma treated with IMRT/3D-CRT.

OBJECTIVES: To analyze the patterns of neck and retropharyngeal lymph nodes (RPLNs) metastases with magnetic resonance imaging (MRI) in patients with sinonasal squamous cell carcinoma (SCC), and to explore the patterns of treatment failure treated with intensity modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT). We also attempt to discuss the role of elective neck irradiation (ENI) in the treatment of cervical negative patients. MATERIALS AND METHODS: Between July 2004 and February 2011, 59 patients with histopathologically proven sinonasal SCC were treated with curative intent at our hospital. Among them, 18 (30.5%) patients had neck or RPLN lymph node involvement at diagnosis. RPLN, level Ib, and level IIa were the most common sites of initial nodal involvement. All patients received IMRT or 3D-CRT, while 19 patients further received surgical resection, and other 40 patients received cisplatin based chemotherapy. Median follow-up durations were 28 months (range, 6-81 months) for the entire patient population and 40 months (range, 7-81 months) among the surviving patients, respectively. RESULTS: The estimated 3-year local-regional control rate, distant-metastasis free survival rate, disease-free survival rate, and overall survival rate were 63.3%, 81.9%, 60.1%, and 68.9%, respectively. On multivariate analysis, old age (>60 years) significantly influenced the overall survival rate(HR=9.428, p=0.000). As for the pattern of treatment failures developed in 26 patients in the follow-up time, local failure, neck recurrence, and distant metastases were seen in 18, 7, and 9 patients, respectively. Level Ib and level IIa were the most common sites of cervical nodal recurrence. None of the 11 patients who received ENI developed failure in the neck. CONCLUSION: For sinonasal SCC patients treated with IMRT or 3D-CRT, our results were generally consistent with findings of other studies, local failure still remain the predominant pattern of treatment failure. However, RPLN metastasis occurred more frequently than previously recognized through detection by MRI in our study. ENI seems to have effectively prevented regional relapse. We recommend ipsilateral level Ib and level IIa neck irradiation for T3-4 sinonasal SCC patients.

The feasibility of omitting irradiation to the contralateral lower neck in stage N1 nasopharyngeal carcinoma patients.

PURPOSE: This study was conducted to analyze the feasibility of omitting irradiation to the contralateral lower neck in stage N1 nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: From July 2008 to January 2012, 52 patients with stage N1 NPC were analyzed. All patients were treated with intensity-modulated radiation therapy (IMRT) and received bilateral upper neck irradiation to levels II, III and VA and ipsilateral lower neck irradiation to levels IV and VB. The contralateral lower neck irradiation was omitted. RESULTS: The median follow-up was 29 months (range, 12-52 months). The 3-year overall survival (OS) rate, progress-free survival (PFS), local failure-free (LFS), nodal recurrence-free survival (NFS) and distant metastasis-free survival (DMFS) rates were 92.2%, 94.1%, 94.3%, 98% and 94.1%, respectively. Only one patient developed a neck recurrence in the irradiation field, while no patients experienced out-of-field nodal recurrence. Univariate analysis suggested that T classification was the only significant prognostic factor for overall survival, and age was significantly associated with PFS. Multivariate analyses indicated that age was also a predictor for overall survival. The elective neck irradiation procedure was not a significant predictor for all of the treatment results. CONCLUSION: Selective irradiation to bilateral levels of II, III and VA and unilateral levels of IV and VB, omitted the contralateral lower neck in a proportion of patients with N1 stage NPC was safe and practicable.

Residual rotational error of X-ray volume imaging system and its dosimetric effect in spinal tumor radiation therapy.

This study was designed to investigate the residual rotational error (RRE) of an X-ray volume imaging (XVI) system and evaluate the dosimetric impact of this error on spinal tumor radiation therapy. Various rotational displacements (set rotations) were applied to an anthropomorphic phantom placed on a HexaPod evo RT CouchTop (HexaPod couch). To detect these set rotations, a series of cone-beam computed tomography (CBCT) scans of the phantom were acquired and registered to the planning CT in the XVI system. The RRE of the XVI system was evaluated by comparing the difference between the set rotations and the registration results from the XVI. The error-introduced plans (by applying the RRE to the copies of the reference plan) were generated in the treatment planning system. The dose distribution was compared between the reference plan and the error-introduced plans to assess the dosimetric impact of RRE. The root-mean-square (RMS) of RREs were 0.31°, 0.35°, and 0.25° in the X (pitch), Y (roll), and Z (yaw) direction, respectively. For the reference plan versus the error-introduced plans, the PTV volumes receiving the prescribed dose (V 100) were 95.1 % versus 94.8-95.7 %; the conformity indices of the PTV were 1.17 versus 1.16-1.19; the minimum dose to 1 cc of volume (D1 cc) of spinal cord were 43.73 Gy versus 43.71-43.89 Gy; the left kidney volumes receiving 15 Gy (V 15) were 29.7 % versus 29.2-30.7 %; and the V 15 values of the right kidney were 26.1 % versus 24.6-27.5 %. Relative to the reference plan, the dose difference of error-introduced plans exceeded 3 % in kidney V 15. In conclusion, the XVI system can accurately detect the rotational displacement. However, large dose deviations were introduced by RREs when organs at risk were away from the iso-center even for small RREs.

Transplantation of oligodendrocyte precursor cells improves locomotion deficits in rats with spinal cord irradiation injury.

Demyelination contributes to the functional impairment of irradiation injured spinal cord. One potential therapeutic strategy involves replacing the myelin-forming cells. Here, we asked whether transplantation of Olig2(+)-GFP(+)-oligodendrocyte precursor cells (OPCs), which are derived from Olig2-GFP-mouse embryonic stem cells (mESCs), could enhance remyelination and functional recovery after spinal cord irradiation injury. We differentiated Olig2-GFP-mESCs into purified Olig2(+)-GFP(+)-OPCs and transplanted them into the rats' cervical 4-5 dorsal spinal cord level at 4 months after irradiation injury. Eight weeks after transplantation, the Olig2(+)-GFP(+)-OPCs survived and integrated into the injured spinal cord. Immunofluorescence analysis showed that the grafted Olig2(+)-GFP(+)-OPCs primarily differentiated into adenomatous polyposis coli (APC(+)) oligodendrocytes (54.6±10.5%). The staining with luxol fast blue, hematoxylin & eosin (LFB/H&E) and electron microscopy demonstrated that the engrafted Olig2(+)-GFP(+)-OPCs attenuated the demyelination resulted from the irradiation. More importantly, the recovery of forelimb locomotor function was enhanced in animals receiving grafts of Olig2(+)-GFP(+)-OPCs. We concluded that OPC transplantation is a feasible therapy to repair the irradiated lesions in the central nervous system (CNS).

Comparison of the NCI-CTCAE version 4.0 and version 3.0 in assessing chemoradiation-induced oral mucositis for locally advanced nasopharyngeal carcinoma.

To compare the role of CTCAE version 4.0 (v4.0) and version 3.0 (v3.0) in assessing chemoradiation-induced oral mucositis (OM) for locally advanced nasopharyngeal carcinoma (LA-NPC). Patients with LA-NPC were recruited into the study. All eligible participants received docetaxel and cisplatin-based induction chemotherapy followed by intensity modulated radiation therapy concurrent with cisplatin. OM was assessed before and weekly during radiotherapy (RT), using CTCAE v3.0 (clinical exam) and v4.0 separately. OM-related quality of life (QOL) was also evaluated in these patients with the EORTC Quality of Life Questionnaire - Head and Neck module (QLQ-H&N35). From June 2010 to February 2011, 23 eligible patients were enrolled. A highly significant correlation (rho=0.838, p=0.000) and a non-significant difference (p=0.167) in OM grades were found between the two CTCAE versions. However, the trend lines showed that the mean grade determined by CTCAE v3.0 reached a plateau while the mean grade determined by v4.0 continued to increase after the fourth week during RT. Changing trends of several QOL subscale mean scores were similar to that of OM mean grade evaluated by CTCAE v4.0. Both grades of the two CTCAE versions were significantly and positively correlated with scores of several QOL subscales. Nonetheless, the correlation coefficients related to CTCAE v4.0 were higher than those related to v3.0 (rho: 0.727-0.865 versus 0.727-0.778). CTCAE v4.0 could serve as a good surrogate for v3.0 (clinical exam) in assessing chemoradiation-induced oral mucositis. Moreover, CTCAE v4.0 has a few subtle advantages over v3.0 under some circumstances such as delegating QOL. However, there is still no "gold standard" assessment scale for oral mucositis. Therefore, the appropriate tool should be carefully chosen according to the purpose of assessment.