Long-term outcomes after particle radiation therapy in patients with nasopharyngeal adenoid cystic carcinoma.

BACKGROUND: Nasopharyngeal adenoid cystic carcinoma (NACC) is a relatively rare salivary gland tumor that is generally associated with poor outcomes. High-dose radiotherapy is a key treatment for patients with NACC. This study reported the long-term efficacy and safety of particle beam radiation therapy (PBRT) for NACC. METHODS AND MATERIALS: Twenty-six patients with nonmetastatic NACC who received definitive PBRT alone were included in this retrospective study. The majority of patients (92.3%) had locally advanced disease. Twenty-five (96.15%) patients received intensity-modulated proton radiotherapy (IMPT) followed by a carbon ion radiotherapy (CIRT) boost, and one patient received CIRT alone. Overall survival (OS), local control (LC), regional control (RC), and distant metastasis control (DMC) rates were calculated via the Kaplan-Meier method. RESULTS: The median follow-up time was 46.95 months for the entire cohort. Seven patients experienced local recurrence, and one patient experience neck lymph node recurrence. The 3- and 4-year OS, LC, RC, and DMC rates were 100% and 91.7%, 92.3% and 84.6%, 95.8% and 87.8%, and 90.2% and 71.3%, respectively. A total of 91.3% of the patients achieved complete remission of gross tumors at 1 year after PBRT. Severe acute toxicity was observed in only two patients. A grade 4 decrease in visual acuity was observed in one patient with orbital apex invasion. No late grade 3 or 5 toxicity was observed. CONCLUSION: Definitive PBRT provided a satisfactory 4-year OS for patients with locally advanced NACC. The toxicity was acceptable and mild. Further follow-up is necessary to confirm the efficacy and safety of definitive PBRT for patients with NACC.

Carbon ion radiotherapy combined with immunotherapy: synergistic anti-tumor efficacy and preliminary investigation of ferroptosis.

Carbon ion radiotherapy (CIRT) may yield satisfactory clinical outcomes for patients who are resistant to radiotherapy. However, the therapeutic impact of carbon ions is still limited in certain recurring or refractory tumors. Therefore, we aimed to evaluate the synergistic anti-tumor effects of immune checkpoint inhibitors (ICIs) in combination with CIRT. We then explored the involvement of ferroptosis in a preliminary investigation. A tumor-bearing mouse model was established, and mice were inoculated subcutaneously with B16-OVA cells into the flanks of both hind legs. Mice were assigned to four groups to receive CIRT, ICIs, or combined treatment. Thereafter, we conducted transcriptome sequencing (RNA-seq), bioinformatics analysis, and various immune-related experiments on the available tumor tissues to investigate differences in the synergistic anticancer effects and potential mechanisms across the groups. The combination therapies significantly improved the survival of mice and inhibited tumor growth, both at local and distant sites. Based on bioinformatics and RNA-seq data, immune-related pathways and genes, immune cell infiltration, and the production of cytokines and chemokines were the most enhanced in the combined treatment group compared to other groups. Finally, we identified a potential role for ferroptosis in the development of local anti-tumor synergy during CIRT combination treatment. In conclusion, this study showed that CIRT and ICIs can enhance the anti-tumor immune effects. We also proposed that ferroptosis may induce anti-tumor effects in CIRT combination therapy, offering a unique perspective on its ability to enhance immunotherapy responses.

Proton radiotherapy in the treatment of IDH-mutant diffuse gliomas: an early experience from shanghai proton and heavy ion center.

PURPOSE: According to the presence or absence of isocitrate dehydrogenase (IDH) mutation, the 2021 WHO classification system bisected diffuse gliomas into IDH-mutant tumors and IDH-wildtype tumors. This study was aimed to evaluate the outcomes of proton radiotherapy treating IDH-mutant diffuse gliomas. PATIENTS AND METHODS: Between May 2015 and May 2022, a total of 52 consecutive patients with IDH-mutant diffuse gliomas were treated at Shanghai Proton and Heavy Ion Center. Tumor histologies were 33 cases of astrocytoma and 19 cases of oligodendroglioma. Tumor classified by WHO grade 2, 3 and 4 were 22, 25, and 5 cases, respectively. All 22 patients with WHO grade 2 tumors and one patient with brain stem WHO grade 4 tumor were irradiated with 54GyE. The other 29 patients with WHO grade 3 and 4 tumors were irradiated with 60GyE. Temozolomide was recommended to all patients, and was eventually conducted in 50 patients. RESULTS: The median follow-up time was 21.7 months. The 12/24-month progression-free survival (PFS) and overall survival (OS) rates for the entire cohort were 97.6%/78.4% and 100%/91.0% group. Examined by both univariate and multivariate analysis, WHO grade of tumor were of the most significant impact for both PFS and OS. No severe acute toxicity (grade 3 or above) was found. In terms of late toxicity, grade 3 radio-necrosis was developed in one case of oligodendroglioma, WHO grade 3. CONCLUSION: Proton radiotherapy produced a favorable outcome with acceptable adverse-effects in patients with IDH-mutant diffuse gliomas.

Particle beam radiotherapy in the treatment of WHO grade 2 and 3 meningiomas: an early experience from Shanghai Proton and Heavy Ion Center.

PURPOSE: To investigate the efficacy and safety of particle beam radiotherapy (PBRT) in the management of patients with WHO grade 2 and 3 meningiomas. METHODS: Thirty-six consecutive and non-selected patients with WHO grade 2 (n = 28) and grade 3 (n = 8) meningiomas were treated at the Shanghai Proton and Heavy Ion Center, from May 2015 to March 2022. The median age of the cohort at PBRT was 48 years. There were 25 and 11 patients treated with PBRT in the setting of newly diagnosed diseases and progressive/recurrent diseases, respectively. PBRT was utilized as re-irradiation in 5 patients. Proton radiotherapy (PRT) and carbon-ion radiotherapy (CIRT), with a median dose of 60 Gy-Equivalent (GyE), were provided to 30 and 6 patients, respectively. RESULTS: With a median follow-up of 23.3 months, the local control rates were 92.0%, 82.0%, and 82.0% at 1, 2, and 3 years for the entire cohort, respectively. Patients with WHO grade 2 meningiomas (100%, 94.1%, 94,1% at 1,2,3 years) had a much better local control than those with WHO grade 3 meningiomas (50%, 25%, 25% at 1,2,3 years; P < 0.001). Three patients, all with WHO grade 3 meningiomas, had deceased at the time of this analysis. Multivariate analyses revealed that WHO grade (grade 2 vs. 3) (p = 0.016) was a significant prognosticator for local control. No severe toxicities (G3 or above) were observed. CONCLUSIONS: Treatment-induced efficacy and toxicities to PBRT in WHO grade 2 and 3 meningiomas were both highly acceptable. Longer follow-up is needed to evaluate the long-term outcome in terms of disease control, survival, as well as potential late effects.

Carbon ion radiation therapy for sinonasal malignancies: Promising results from 2282 cases from the real world.

The aim of this study is to compare the effectiveness of carbon ion radiation therapy (CIRT), proton radiation therapy (PRT), and photon-based intensity-modulated radiation therapy (IMRT) in the treatment of sinonasal malignancies. We identified studies through systematic review and divided them into three cohorts (CIRT group/PRT group/IMRT group). Primary outcomes of interest were overall survival (OS) and local control (LC). We pooled the outcomes with meta-analysis and compared the survival difference among groups using Chi2 (χ2 ) test. A representative sample of 2282 patients with sinonasal malignancies (911 in the CIRT group, 599 in the PRT group, and 772 in the IMRT group) from 44 observation studies (7 CIRT, 16 PRT, and 21 IMRT) was included. The pooled 3-year OS, LC, distant metastasis-free survival, and progression-free survival rates were 67.0%, 72.8%, 69.4%, and 52.8%, respectively. Through cross-group analysis, the OS was significantly higher after CIRT (75.1%, 95% CI: 67.1%-83.2%) than PRT (66.2%, 95% CI: 57.7%-74.6%; χ2  = 13.374, P < .0001) or IMRT (63.8%, 95% CI: 55.3%-72.3%; χ2  = 23.814, P < .0001). LC was significantly higher after CIRT (80.2%, 95% CI: 73.9%-86.5%) than PRT (72.9%, 95% CI: 63.7%-82.0%; χ2  = 8.955, P = .003) or IMRT (67.8%, 95% CI: 59.4%-76.2%; χ2  = 30.955, P < .0001). However, no significant difference between PRT and IMRT for OS and LC was observed. CIRT appeared to provide better OS and LC for patients with malignancies of nasal cavity and paranasal sinuses. A prospective randomized clinical trial is needed to confirm the superiority of CIRT in the treatment of sinonasal tumors.

Particle radiation therapy in the management of malignant glioma: Early experience at the Shanghai Proton and Heavy Ion Center.

BACKGROUND: The objective of this study was to evaluate the outcomes of patients with high-grade glioma who received treatment with particle radiotherapy. METHODS: Between June 2015 and October 2018, 50 consecutive and nonselected patients with glioblastoma multiforme (n = 34) or anaplastic glioma (n = 16) were treated at the Shanghai Proton and Heavy Ion Center. Twenty-four patients received proton radiotherapy (at a dose of 60 gray-equivalents in 30 daily fractions), and 26 patients received proton radiotherapy plus a carbon-ion radiotherapy (CIRT) boost in various dose-escalating schemes. All patients received temozolomide because of their age or their O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Progression-free survival (PFS) and overall survival (OS) rates, as well as treatment-induced toxicities, were analyzed. RESULTS: At a median follow-up of 14.3 months (range, 4.8-39.6 months), the 12-month and 18-month OS rates were 87.8% (95% CI, 77.6%-98.0%) and 72.8% (95% CI, 56.7%-88.9%), respectively, and the 12-month and 18-month PFS rates were 74.2% (95% CI, 60.9%-87.5%) and 59.8% (95% CI, 43.1%-76.5%), respectively. Univariate analyses revealed that age (>50 vs ≤50 years), World Health Organization grade (3 vs 4), and Karnofsky performance status (>80 vs ≤80) were significant prognosticators for OS, and IDH mutation and World Health Organization grade were significant for predicting PFS. Furthermore, MGMT promoter methylation, performance status, and age showed a trend toward predicting PFS. No significant predictive factors for PFS or OS were identified in multivariate analyses. Twenty-nine patients experienced grade 1 treatment-related acute adverse effects, and 11 developed grade 1 (n = 6) or grade 2 (n = 5) late adverse effect of radiation-induced brain necrosis. No grade 3, 4, or 5 toxicities were observed. CONCLUSIONS: Particle radiotherapy produced 18-month OS and PFS rates of 72.8% and 59.8%, respectively, with acceptable adverse effects in patients with high-grade glioma. Particle radiotherapy at a dose ≥60 gray-equivalents appears to be safe and potentially effective.

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.

Outcomes of orbital malignancies treated with eye-sparing surgery and adjuvant particle radiotherapy: a retrospective study.

BACKGROUND: To report the clinical experience of eye sparing surgery (ESS) and adjuvant carbon-ion or proton radiotherapy (CIRT or PRT) for orbital malignancies. METHODS: An analysis of the retrospective data registry from the Shanghai Proton and Heavy Ion Center for patients with orbital tumors was conducted. The 2-year local progression-free, regional recurrence-free, distant metastasis-free, progression-free, and overall survival (LPFS, RRFS, DMFS, PFS, OS) rates as well as associated prognostic indicators were analyzed. Radiotherapy-induced acute and late toxicities were summarized. RESULTS: Between 7/2014 to 5/2018, 22 patients with orbital malignancies of various pathologies received ESS followed by CIRT (18), PRT (1), or PRT + CIRT boost (3). With a median follow-up of 20.25 (range 3.8-38.8) months, the 2-year OS, PFS, LPFS, RRFS, and DMFS rates were 100, 57.9, 92.9, 93.3, and 72.8%, respectively. No acute severe (i.e., ≥grade 3) toxicity was observed. Two patients experienced severe visual impairment as late toxicities. CONCLUSION: With few observed acute and late toxicities, particle radiotherapy following ESS provided effective local control with infrequent severe toxicities for patients with orbital malignancies.

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.

Over-expression of platelet-derived growth factor-D promotes tumor growth and invasion in endometrial cancer.

The platelet-derived growth factor-D (PDGF-D) was demonstrated to be able to promote tumor growth and invasion in human malignancies. However, little is known about its roles in endometrial cancer. In the present study, we investigated the expression and functions of PDGF-D in human endometrial cancer. Alterations of PDGF-D mRNA and protein were determined by real time PCR, western blot and immunohistochemical staining. Up-regulation of PDGF-D was achieved by stably transfecting the pcDNA3-PDGF-D plasmids into ECC-1 cells; and knockdown of PDGF-D was achieved by transient transfection with siRNA-PDGF-D into Ishikawa cells. The MTT assay, colony formation assay and Transwell assay were used to detect the effects of PDGF-D on cellular proliferation and invasion. The xenograft assay was used to investigate the functions of PDGF-D in vivo. Compared to normal endometrium, more than 50% cancer samples showed over-expression of PDGF-D (p < 0.001), and high level of PDGF-D was correlated with late stage (p = 0.003), deep myometrium invasion (p < 0.001) and lympha vascular space invasion (p = 0.006). In vitro, over-expressing PDGF-D in ECC-1 cells significantly accelerated tumor growth and promoted cellular invasion by increasing the level of MMP2 and MMP9; while silencing PDGF-D in Ishikawa cells impaired cell proliferation and inhibited the invasion, through suppressing the expression of MMP2 and MMP9. Moreover, we also demonstrated that over-expressed PDGF-D could induce EMT and knockdown of PDGF-D blocked the EMT transition. Consistently, in xenografts assay, PDGF-D over-expression significantly promoted tumor growth and tumor weights. We demonstrated that PDGF-D was commonly over-expressed in endometrial cancer, which was associated with late stage deep myometrium invasion and lympha vascular space invasion. Both in vitro and in vivo experiments showed PDGF-D could promote tumor growth and invasion through up-regulating MMP2/9 and inducing EMT. Thus, we propose targeting PDGF-D to be a potent strategy for endometrial cancer treatment.

A protocol for a randomized trial evaluating the role of carbon-ion radiation therapy plus camrelizumab for patients with locoregionally recurrent nasopharyngeal carcinoma.

PURPOSE: Management of locoregionally recurrent nasopharyngeal carcinoma (LR NPC) is difficult. Although carbon-ion radiation therapy (CIRT) could substantially improve the overall survival (OS) of those patients, around 40% of the patients may still develop local failure. Further improvement of the disease control is necessary. Immunotherapy, such as immune checkpoint inhibitors (ICIs) becomes a promising antitumor treatment. The role of ICIs was proved in head and neck cancers including recurrent/metastatic NPC. Preclinical studies indicated potential synergistic effects between radiation therapy and ICIs. Therefore, we conduct a randomized phase 2 trial to evaluate the efficacy and safety of camrelizumab, an anti-PD-1 monoclonal antibody, along with CIRT in patients with LR NPC. METHODS: Patients will be randomly assigned at 1:1 to receive either standard CIRT with 63 Gy (relatively biological effectiveness, [RBE]) in 21 fractions, or standard CIRT plus concurrent camrelizumab. Camrelizumab will be administered intravenously with a dose of 200 mg, every 2 week, for a maximum of 1 year. We estimate addition of camrelizumab will improve the 2-year progression-free survival (PFS) from 45% to 60%. A total of 146 patients (with a 5% lost to follow-up rate) is required to yield a type I error of 0.2, and a power of 0.8. RESULTS AND CONCLUSION: The results of the trial may shed insights on the combined therapy with ICIs and CIRT.

Tumor volume instead of recurrent T category predicts clinical outcome of patients with locally recurrent nasopharyngeal carcinoma salvaged by carbon ion radiation therapy.

BACKGROUND: Although carbon ion radiation therapy (CIRT) substantially improves the overall survival (OS) of patients with LR-NPC, approximately 40% of the patients may develop local recurrence. The purpose of study is to assess the value of tumor volume (TV) as a predictive tool to guide individualized CIRT. METHODS: Consecutive patients with LR-NPC treated using CIRT at Shanghai Proton and Heavy Ion Center between April 2015 and May 2019 were included. TV before CIRT was delineated and calculated. The generalized additive Cox model was used to examine the relationship between TV and OS and local progression-free survival (LPFS). A cutoff value of tumor volume was identified to best discriminate patients with different 2-year OS rates, using receiver operating characteristic (ROC) analysis. RESULTS: A total of 157 patients were enrolled. The median tumor volume was 22.49 (2.52-90.13) ml. In the univariable analyses, tumor volume was significantly associated with OS (p < 0.001) and LPFS (p = 0.01). The relationships with OS (p = 0.009) and LPFS (p = 0.020) remained significant in multivariable analyses. Using ROC analysis, a TV of 26.69 ml was identified to predict the 2-year OS rate. To facilitate potential clinical use, 25 ml was designated as the final cutoff value. The 2-year OS and LPFS rates were 88.6 % vs 62.3 %, and 54.7 % vs 35.5 %, for patients with a TV ≤ 25 ml and > 25 ml, respectively. CONCLUSION: Tumor volume could predict the OS and LPFS of patients. We propose that tumor volume should be considered in the risk stratification and CIRT-based treatment for patients with LR-NPC.

Preliminary clinical outcomes of head and neck squamous cell carcinoma treated with particle beam radiation therapy.

PURPOSE: Further improvement in clinical outcomes is needed for patients with head and neck squamous cell carcinoma (HNSCC), as there is typically a poor prognosis at diagnosis. This study aimed to report the preliminary therapeutic outcomes and side effects in patients with HNSCC receiving particle beam radiotherapy (PBRT), owing to the physical and biological advantages of this approach. METHODS: We retrospectively analyzed 68 patients with newly diagnosed HNSCC who received PBRT at the Shanghai Proton and Heavy Ion Center (SPHIC) between August 2015 and December 2020. The Kaplan-Meier approach was used to determine overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS). Common Terminology Criteria for Adverse Events (CTCAE) 4.03 was also used to grade acute and late toxicities. RESULTS: With a median follow-up time of 24.5 months (range, 3-65), the 3-year OS, DSS, PFS, LRFS, RRFS, and DMFS rates for the entire cohort were 79.0%, 84.7%, 67.9%, 83.5%, 83.3%, and 96.1%, respectively. Univariate and multivariate analyses showed that N category was a significant predictor of OS, PFS, and RRFS. In terms of acute toxicities, two patients demonstrated severe mucositis or dysphagia, and two patients also displayed a late toxicity of significant mucosal necrosis. CONCLUSION: These findings suggest that PBRT can provide patients with HNSCC with a promising therapeutic benefit and manageable toxicity. Prospective evaluation of clinical outcomes with PBRT for HNSCC is warranted, with an emphasis on clinical effectiveness as well as adverse effects and patient quality of life.

Pre-treatment FLT-PET parameters as a prognostic tool for patients with locally advanced recurrent nasopharyngeal carcinoma salvaged by carbon-ion radiotherapy: a pilot study.

Background: Although carbon-ion radiotherapy (CIRT) may improve outcome for patients with locoregionally recurrent nasopharyngeal carcinoma (LR-NPC), local progression still remains one of the major failure patterns. This suggests an unmet need of markers for predicting disease control after re-irradiation and potentially guiding tailored treatment. The purpose of this study was to explore the predictive value of pre-treatment 3'-deoxy-3'-[18F]fluorothymidine (FLT)-positron emission tomography (PET) for patients with locally advanced LR-NPC. Methods: In this retrospective analysis, LR-NPC patients with locally advanced stage (stage III/IV) who received pre-treatment FLT-PET between June, 2015, and August, 2017, were retrospective reviewed and included in this study. OS and local progression-free survival (LPFS) were calculated using the Kaplan-Meier method. Univariable and multivariable Cox regression analyses of LPFS were performed. FLT-derived parameters, including SUVmax, metabolic tumor volume (MTV), and total lesion thymidine (TLT) were examined. The relationship between FLT-derived parameters and mucosal necrosis was tested by the Wilcoxon test. Results: A total of 27 patients with a median follow-up of 31.3 months were included in this analysis. The 2-year OS and LPFS rates were 85.2% and 47.9%, respectively. In multivariable analysis, except for TLT-40% (P=0.059), all pre-treatment MTVs (P=0.040 for MTV-40%; P=0.021 for MTV-50%; P=0.026 for MTV-60%) and TLTs (P=0.043 for TLT-50%; P=0.048 for TLT-60%) were significantly related to LPFS. Moreover, MTVs and TLTs with various boundaries (except for MTV-40%) were also associated with the development of mucosal necrosis after CIRT. Conclusions: In the current study, a significant association between pre-treatment FLT-PET and LPFS was observed in patients with locally advanced LR-NPC. Further investigations are warranted to confirm the predictive role of FLT-PET.

Comparison of the efficacy and toxicity of postoperative proton versus carbon ion radiotherapy for head and neck cancers.

Background: To compare the efficacy and toxicity of adjuvant proton beam vs. carbon-ion beam radiotherapy for head and neck cancers after radical resection and to explore the value of particle beam radiotherapy (PBRT) in postoperative radiotherapy for head and neck cancers. Methods: Data from 38 head and neck cancer patients who received adjuvant PBRT after complete surgical resection at the Shanghai Proton and Heavy Ion Center (SPHIC) between October 2015 and March 2019 were retrospectively analyzed. In total, 18 patients received adjuvant proton beam therapy (54-60 GyE/27-30 fractions) and 20 received adjuvant carbon-ion radiotherapy (CIRT) (54-60 GyE/18-20 fractions). Survival rates were calculated using Kaplan-Meier analysis. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Effects (version 4.03). Results: With a median follow-up time of 21 (range, 3-45) months, the 2-year overall survival (OS), progression-free survival (PFS), local-regional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) rates were 93.3%, 87.4%, 94.1%, and 90.7%, respectively, for the entire cohort. The rates after proton beam therapy vs. CIRT were 94.1% vs. 91.7% (P=0.96), 88.1% vs. 86.2% (P=0.96), 94.4% vs. 93.3% (P=0.97), and 88.1% vs. 92.9% (P=0.57), respectively. Furthermore, 16 of the 18 (88.9%) patients developed acute grade I/II dermatitis (13 grade I; 3 grade II) after proton beam therapy, and only 7 of the 20 (35%) patients developed acute grade I dermatitis after CIRT (P=0.001). The incidence of acute grade I/II mucositis and xerostomia in proton and carbon ion cases were 45% vs. 55% (P=0.75) and 56% vs. 50% (P=0.87) respectively. Conclusions: Adjuvant proton beam therapy and CIRT after radical surgical resection for head and neck cancers provided satisfactory therapeutic effectiveness, but no significant difference was observed between the two radiotherapy technologies. However, adjuvant CIRT was associated with a more favorable acute toxicity profile as compared to proton beam therapy with significantly lower frequency and severity of acute dermatitis observed.

Carbon-ion radiotherapy boost with standard dose proton radiation for incomplete-resected high-grade glioma: a phase 1 study.

Background: To investigate the maximal tolerated dose (MTD) of a carbon-ion radiotherapy (CIRT) boost prior to standard dose proton radiotherapy (PRT) for newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA) patients with residual lesion after resection. Methods: In total, 18 patients with high-grade glioma (HGG) (16 with GBM and 2 with AA) were enrolled in a prospective 3×3 design phase 1 trial. We investigated four dose-levels of CIRT boost [9 (starting level), 12, 15, and 18 Gy relative biological effectiveness (RBE)] delivered in three equal fractions prior to the standard dose PRT (60 Gy RBE in 30 fractions). Concurrent temozolomide (TMZ) was not provided during the CIRT boost but was initiated on the first day of PRT. Acute and late toxicities were scored based on the Common Terminology Criteria for Adverse Events (CTCAE, v 4.03). Dose-limiting toxicities (DLTs) were defined as radiation-induced severe toxicities (≥ grade 3). Results: With a median follow-up of 17.9 months, no severe (≥ grade 3) acute or late toxicities were observed in patients treated with the first three dose levels (CIRT boost doses of 9, 12, 15 Gy RBE). Severe late toxicity (grade 3 radiation necrosis) was observed in the first patient treated with the 18 Gy RBE CIRT boost level. Therefore, this trial was terminated and the MTD of the induction CIRT boost was determined at 15 Gy RBE in 3 fractions. At the time of this analysis, both patients with AA were alive without disease progression. The progression-free survival (PFS) and overall survival (OS) for GBM at 12 months were 50.6% and 78.6%, respectively. Conclusions: Particle beam radiotherapy consisting of a CIRT boost of 15 Gy RBE (in 3 fractions) following standard dose PRT (60 Gy RBE in 30 fractions), and used in conjunction with TMZ, is safe and potentially effective for patients with HGG.

Intensity-modulated proton and carbon-ion radiation therapy in the management of major salivary gland carcinomas.

Background: Primary major salivary gland carcinomas (SGCs) present with diverse histological types that are known to be largely radioresistant with a high tendency to develop distant metastasis (DM). Photon-based radiotherapy (RT) is limited in terms of its therapeutic effect and toxicities. In view of the physical and biological advantages of intensity-modulated proton and/or carbon-ion radiation therapy, we aimed to evaluate the short-term therapeutic effect and toxicities in patients with major SGCs treated with this form of radiation therapy. Methods: Between August 2015 and November 2019, a total of 55 consecutive and non-selected major SGC patients who received particle RT at the Shanghai Proton and Heavy Ion Center (SPHIC) were retrospectively analyzed. The 2-year overall survival (OS), progression-free survival (PFS), local-regional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) rates, as well as prognostic factors were analyzed. Additionally, acute and late toxicities were also analyzed. Results: With a median follow-up time of 24 (range, 6-57) months, the 2-year OS, PFS, LRRFS, and DMFS rates were 91.6%, 78.6%, 94.2%, and 83.9%, respectively. At the time of this analysis, four patients had developed local or regional recurrence, and seven additional patients had developed DM. Three patients had died due to disease progression, and another patient with recurrence experienced a late Grade 5 event (hemorrhage) at 9 months after re-irradiation with carbon ion and subsequently died. Otherwise, none of the patients had grade 3 or higher treatment-induced acute or late adverse effects except one who developed grade 3 acute mucositis. Conclusions: Overall, intensity-modulated proton and/or carbon-ion radiation therapy provided satisfactory therapeutic effectiveness in our major SGCs patients with a low incidence of acute and late toxicities.

The role of carbon-ion radiotherapy in the treatment of adenoid cystic carcinoma of the nasopharynx.

Background: Nasopharyngeal adenoid cystic carcinoma (NACC) is a distinct subgroup of adenoid cystic carcinoma (ACC) with limited surgical access but predilection of regional and distant metastasis. Although radiotherapy is an integral treatment for patients with NACC, photon-based radiotherapy yielded suboptimal local control. Because of its advantages in biology and physics properties, carbon-ion radiotherapy (CIRT) was attempted for the treatment of head and neck ACC; however, the use of CIRT specifically for NACC has not been investigated. Methods: Patients with NACC that received CIRT alone or a combination of CIRT and proton beam therapy (PBT) at the Shanghai Proton and Heavy Ion Center (SPHIC) between July 2016 and March 2019 were included in the analysis. Patients with newly diagnosed NACC received combined therapy of CIRT (as boost) and PBT, and those with recurrent disease received CIRT alone. Overall survival (OS), local progression-free survival (LPFS), regional progression-free survival (RPFS), and distant metastasis-free survival (DMFS) were calculated by Kaplan-Meier method. Results: A total of 22 patients were included in this analysis. Among those, 18 patients had newly diagnosed NACC (17 with locally advanced disease), and 4 had recurrent NACC including 2 failed previous irradiation. After a median follow-up of 30.9 months, the 2-year OS rate, PFS rate, LPFS rate, RPFS rate and DMFS rate were 100%, 84.8%, 94.4%, 100%, and 84.8%, respectively. Three patients experienced grade 3 mucositis or xerostomia. No late toxicity of grade ≥3 was observed. Conclusions: CIRT alone or in combination with PBT appeared to be a promising modality for the treatment of NACC and produced satisfactory local disease control and toxicity profile. Distant metastasis remained to be a substantial mode for treatment failure. Further follow-up is necessary to evaluate long-term survivals and late toxicity profile.

Perfusion MR prior to radiotherapy is a strong predictor of survival in high-grade gliomas after proton and carbon ion radiotherapy.

Background: To assess the survival predictability of perfusion magnetic resonance imaging (MRI) by the normalized cerebral blood volume (nCBV) prior to particle beam radiotherapy (PBRT) in high-grade glioma (HGG) patients underwent particle therapy. Methods: The study retrieved dynamic susceptibility contrast MRI acquired prior to PBRT between 6/2015 and 3/2019 in 45 patients with HGG. Maximum nCBV (nCBVmax) within or adjacent to surgical/tumor bed was measured using 'hot-spot' method. The predictive values of nCBVmax for progression-free survival (PFS) and overall survival (OS) were assessed in univariate Kaplan-Meier curve and multivariate Cox proportional hazards (CPH) models. Nomograms based on CPH results were constructed to individualize the predicted probability of OS and PFS. Results: The Kaplan-Meier curves and all CPH models based on nCBVmax as continuous variable (nCBVmax-C), group by cut-off derived from median value and Youden-index method showed that nCBVmax prior to radiotherapy was a strong predictor for both PFS and OS in HGG patients who underwent PBRT. Nomograms built on CPH models showed similar excellent performance in both discrimination and calibration. Conclusions: Perfusion imaging prior to PBRT is a strong predictor of survival in HGG. Novel perfusion MR-based nomogram with prospective validation could potentially be formally used in future clinical practice to individualize survival probability.

Particle beam radiation therapy for head and neck rhabdomyosarcoma in adults.

Background: Rhabdomyosarcoma (RMS) is rare in adults, with a significantly worse prognosis than its pediatric counterpart. Radiotherapy (RT) plays a significant role in treating head and neck RMS (HNRMS), but the outcomes of conventional RT are limited by the complex anatomy and unfavorable pathology subtypes of the adult H&N RMS. Here, we aim to report the effectiveness and safety of carbon-ion beam RT (CIRT), either alone or in combination with proton radiotherapy (PRT) in the management of adult HNRMS. Methods: Fifteen adult patients with HNRMS were enrolled on a prospective registry protocol between 06/2015 and 12/2019. Eight patients presented with parameningeal tumors, and eight had unfavorable pathology subtypes [alveolar =7, not otherwise specified (NOS) =1]. Eleven patients had gross tumors before the start of RT (volume range, 46.1-137.6 cm3). Two patients failed the earlier RT. All except for one patient received multi-drug chemotherapy. The median absolute dose of particle beam RT was 70.0 Gy [relative biological effectiveness (RBE)]. Results: With a median follow-up of 21 months, local or distant recurrence occurred in three and four patients, respectively, and two added patients had both local and distant failure. One patient died of distant metastasis (DM), and another died of an unrelated condition. The 1- and 2-year overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) rates were 87.5% and 70.0%, 92.3% and 67.1%, 72.2% and 54.2%, and 65.0% and 24.4%, respectively, for the entire cohort. Both patients who failed earlier RT and received salvage CIRT developed DM but were alive at last follow-up. No acute toxicity of ≥ grade 3 or late toxicity of ≥ grade 2 was observed. Conclusions: CIRT, either used alone or in combination with PRT, is not only feasible and safe but also useful in local disease control for HNRMS. DM is the most important cause of treatment failure; thus, more effective systemic treatment is needed to improve the prognosis of HNRMS further.