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

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          Abstract

          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.

          Abstract

          Reirradiation for locoregionally recurrent nasopharyngeal carcinoma after a definitive dose of radiotherapy is challenging and usually associated with severe toxicities. Carbon ion radiotherapy provides promising short‐term survival rates for patients with locoregionally recurrent nasopharyngeal carcinoma, with few treatment‐induced severe adverse effects noted.

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          Most cited references27

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          Management of Nasopharyngeal Carcinoma: Current Practice and Future Perspective.

          Nasopharyngeal carcinoma of the undifferentiated subtype is endemic to southern China, and patient prognosis has improved significantly over the past three decades because of advances in disease management, diagnostic imaging, radiotherapy technology, and broader application of systemic therapy. Despite the excellent local control with modern radiotherapy, distant failure remains a key challenge. Advances in molecular technology have helped to decipher the molecular pathogenesis of nasopharyngeal carcinoma as well as its etiologic association with the Epstein-Barr virus. This in turn has led to the discovery of novel biomarkers and drug targets, rendering this cancer site a current focus for new drug development. This article reviews and appraises the key literature on the current management of nasopharyngeal carcinoma and future directions in clinical research.
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            Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice.

            In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤ 500 ms) of radiation delivered at ultrahigh dose rate (≥ 40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤ 0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc(+) orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-β (transforming growth factor-β) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor-α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.
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              Long-term survival analysis of nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA levels.

              The objective of this study was to confirm the relation between plasma Epstein-Barr virus (EBV) DNA (pEBV DNA) load and treatment outcomes after long-term follow-up in patients with nasopharyngeal carcinoma (NPC). In total, 210 patients with NPC were enrolled, including 99 previously reported patients and 111 new patients. They prospectively received treatment with induction chemotherapy plus radiotherapy and were followed for at least 6 years. In these patients, pEBV DNA levels were measured before treatment and 1 week after treatment. The plasma viral load was correlated with treatment outcomes in the group of new patients and in the entire group. By using previously defined pEBV DNA cutoff values (1500 copies/mL pretreatment and 0 copies/mL post-treatment), there was a significant correlation between the pEBV DNA value and relapse-free survival, overall survival, and subsequent relapse rates in the new, independent patient cohort. Outcome analyses for the entire group revealed a higher relapse rate (45.6% vs 21.5% [P = .0037] or 76.7% vs 26.1% [P < .0001]), a worse relapse-free survival rate (56.5% vs 79.3% [P < .0001] or 23.3% vs 75.6% [P < .0001]), and poorer overall survival (59.2% vs 86% [P = .0003] or 33.3% vs 79.4% [P < .0001]) in patients who had high pretreatment or persistently detectable post-treatment pEBV DNA levels, respectively, versus their respective counterparts. Multivariate Cox analysis also confirmed these results. In this expanded study, the prognostic significance of pEBV DNA was confirmed using predefined cutoff values in an independent patient group, and pEBV DNA was identified as an independent prognostic marker for NPC. Copyright © 2012 American Cancer Society.
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                Author and article information

                Contributors
                lin.kong@sphic.org.cn
                jiade.lu@sphic.org.cn
                Journal
                Cancer
                Cancer
                10.1002/(ISSN)1097-0142
                CNCR
                Cancer
                John Wiley and Sons Inc. (Hoboken )
                0008-543X
                1097-0142
                26 March 2018
                01 June 2018
                : 124
                : 11 ( doiID: 10.1002/cncr.v124.11 )
                : 2427-2437
                Affiliations
                [ 1 ] Department of Radiation Oncology Shanghai Proton and Heavy Ion Center Shanghai China
                [ 2 ] Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center Fudan University Cancer Hospital Shanghai China
                Author notes
                [*] [* ] Corresponding authors: Jiade J. Lu, MD, MBA, Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, 4365 Kangxin Rd, Pudong, Shanghai, 201321, China; jiade.lu@ 123456sphic.org.cn ; and Lin Kong, MD, Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, 4365 Kangxin Rd, Pudong, Shanghai, 201321, China; lin.kong@ 123456sphic.org.cn
                Author information
                http://orcid.org/0000-0001-6637-1814
                Article
                CNCR31318
                10.1002/cncr.31318
                6001443
                29579324
                653de394-c4d6-4a8d-8bab-b20303c7f186
                © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 23 October 2017
                : 28 December 2017
                : 08 January 2018
                Page count
                Figures: 4, Tables: 5, Pages: 11, Words: 6687
                Funding
                Funded by: National Key Research and Development Program of China
                Award ID: 2017YFC0108603
                Funded by: Joint Breakthrough Project for New Frontier Technologies of the Shanghai Hospital Development Center
                Award ID: SHDC 12015118
                Award ID: Project No. SHDC 12015118
                Funded by: Science and Technology Commission of Shanghai Municipality
                Award ID: 15411950102
                Award ID: 15411950106
                Categories
                Original Article
                Original Articles
                Discipline
                Radiation Oncology
                Custom metadata
                2.0
                cncr31318
                June 1, 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.1.1 mode:remove_FC converted:14.06.2018

                Oncology & Radiotherapy
                intensity‐modulated carbon ion radiotherapy,recurrent nasopharyngeal carcinoma,reirradiation,survival,toxicity

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