A Multicenter Study of Carbon Ion Radiotherapy for Mucosal Melanoma of the Head and Neck Sub analysis of the Japan Carbon Ion Radiotherapy Study Group (J CROS) Study (1402 HN) Accepted Manuscript A Mu[.]
Accepted Manuscript A Multicenter Study of Carbon-Ion Radiotherapy for Mucosal Melanoma of the Head and Neck: Sub-analysis of the Japan Carbon-Ion Radiotherapy Study Group (JCROS) Study (1402 HN) Masashi Koto, MD, PhD, Yusuke Demizu, MD, PhD, Jun-ichi Saitoh, MD, PhD, Hiroaki Suefuji, MD, PhD, Hiroshi Tsuji, MD, PhD, Tomoaki Okimoto, MD, PhD, Tatsuya Ohno, MD, PhD, Yoshiyuki Shioyama, MD, PhD, Ryo Takagi, DDS, PhD, Kenji Nemoto, MD, PhD, Takashi Nakano, MD, PhD, Tadashi Kamada, MD, PhD PII: S0360-3016(16)33602-1 DOI: 10.1016/j.ijrobp.2016.12.028 Reference: ROB 23974 To appear in: International Journal of Radiation Oncology • Biology • Physics Received Date: 15 August 2016 Revised Date: 15 November 2016 Accepted Date: 18 December 2016 Please cite this article as: Koto M, Demizu Y, Saitoh J-i, Suefuji H, Tsuji H, Okimoto T, Ohno T, Shioyama Y, Takagi R, Nemoto K, Nakano T, Kamada T, and the Japan Carbon Ion Radiotherapy Study Group, A Multicenter Study of Carbon-Ion Radiotherapy for Mucosal Melanoma of the Head and Neck: Sub-analysis of the Japan Carbon-Ion Radiotherapy Study Group (J-CROS) Study (1402 HN), International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/ j.ijrobp.2016.12.028 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT A Multicenter Study of Carbon-Ion Radiotherapy for Mucosal Melanoma of the Head and Neck: Sub-analysis of the Japan Carbon-Ion RI PT Radiotherapy Study Group (J-CROS) Study (1402 HN) Short title: C-ion RT for mucosal melanoma of H&N SC Masashi Koto, MD, PhD ∗, Yusuke Demizu, MD, PhD†, Jun-ichi Saitoh, MD, M AN U PhD‡; Hiroaki Suefuji, MD, PhD§; Hiroshi Tsuji MD, PhD∗; Tomoaki Okimoto MD, PhD†; Tatsuya Ohno MD, PhD‡, Yoshiyuki Shioyama, MD, PhD§, Ryo Takagi, DDS, PhD∗, Kenji Nemoto, MD, PhD‖, Takashi Nakano, MD, PhD‡, Tadashi Kamada, MD, PhD∗, and the Japan Carbon Ion ∗ TE D Radiotherapy Study Group Hospital of the National Institute of Radiological Sciences, National EP Institutes for Quantum and Radiological Sciences and Technology, † AC C Chiba, Japan Department of Radiology, Hyogo Ion Beam Medical Center, Tatsuno, Japan ‡ Gunma University Heavy Ion Medical Center, Maebashi, Japan § Ion Beam Therapy Center, SAGA-HIMAT Foundation, Tosu, Japan ‖ Department of Radiation Oncology, Yamagata University Faculty of Medicine, Yamagata, Japan ACCEPTED MANUSCRIPT Corresponding author: Masashi Koto, Hospital of the National Institute of Radiological Sciences, National Institutes for Quantum and RI PT Radiological Sciences and Technology 4-9-1 Anagawa, Inage-ku 263-8555 Chiba, Japan Tel: +81-43-206-3360; Fax: SC +81-43-256-6506; E-mail: koto.masashi@qst.go.jp M AN U Conflict of interest: none Funding: This research did not receive any specific grant from funding AC C EP TE D agencies in the public, commercial, or not-for-profit sectors ACCEPTED MANUSCRIPT Summary Mucosal melanoma of the head and neck is a rare, radioresistant tumor RI PT This retrospective multicenter study evaluated the effectiveness and safety of carbon-ion radiotherapy for 260 patients with mucosal SC melanoma of the head and neck Carbon-ion radiotherapy resulted in AC C EP TE D M AN U good local control and overall survival with acceptable toxicities ACCEPTED MANUSCRIPT A Multicenter Study of Carbon-Ion Radiotherapy for Mucosal Melanoma of the Head and Neck: Sub-analysis of the xxxx RI PT Short title: C-ion RT for mucosal melanoma of H&N SC Conflict of interest: None M AN U Funding: This research did not receive any specific grant from funding AC C EP TE D agencies in the public, commercial, or not-for-profit sectors ACCEPTED MANUSCRIPT Abstract Purpose: The prognosis of patients with mucosal melanoma of the RI PT head and neck (MMHN) is poor, even for those with operable tumors, because of frequent local recurrence and metastasis We evaluated the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for MMHN in SC the xxxx M AN U Methods and Materials: MMHN patients with N0-1M0 status who were treated with C-ion RT at institutions in xxxx between November 2003 and December 2014 were analyzed retrospectively Two hundred and sixty patients (male, 111; female, 149; median age, 68 years) with TE D histologically proven MMHN were enrolled Results: Primary sites included the nasal cavity in 178 patients, paranasal sinuses in 43, oral cavity in 27, and pharynx in 12 Eighty-six EP patients had T3 tumors, 147 had T4a tumors, and 27 had T4b tumors Two hundred and fifty-one patients were diagnosed with N0 disease, AC C and with N1 disease The median total dose and number of fractions were 57.6 Gy RBE (relative biological effectiveness) and 16, respectively Chemotherapy including dimethyl traizeno imidazole carboxamide was used concurrently in 129 patients The median follow-up duration was 22 months (range, 1–132 months) The 2-year overall survival and local control rates were 69.4% and 83.9%, respectively Multivariate analysis showed that gross tumor volume ACCEPTED MANUSCRIPT and concurrent chemotherapy were significant prognostic factors for overall survival Grade and Grade late morbidities were observed in 27 and patients (5 developed ipsilateral blindness, mucosal ulcer, No patients developed Grade late morbidities RI PT and second malignant disease in the irradiated volume), respectively AC C EP TE D M AN U SC Conclusion: C-ion RT is a promising treatment option for MMHN ACCEPTED MANUSCRIPT Introduction Mucosal melanoma of the head and neck (MMHN) is an infrequent RI PT tumor comprising ~10% of melanomas arising in the head and neck and ~1% of all malignant melanomas (1-3) MMHN constitutes a greater proportion of all melanomas in Japanese patients (8%) than it SC does in Caucasians (1%), although cutaneous melanoma is 10 times M AN U less frequent in Japanese patients than in Caucasians (4, 5) According to the US National Cancer Database, the incidence of MMHN has remained stable between 1985 and 1994, despite an increase in the incidence of cutaneous melanoma (1) Jangard et al reported that in significantly (6) TE D Sweden, between 1960 and 2000, the incidence of MMHN increased MMHN is typically aggressive, resulting in poor prognosis In the EP Surveillance, Epidemiology, and End Results registry, Jethanamest et al (7) reported that between 1973 and 2007, the 5-year overall AC C survival (OS) of 815 MMHN cases was 25.2% Radical local excision for MMHN was once considered curative, although the prognosis was generally grave Even in patients with operable tumors, the 5-year OS was limited to 25–46% (8) Although MMHN is known to be radioresistant, radiotherapy has become a widely used option as part of the treatment algorithm in an adjuvant and definitive setting In a small study, high total dose and hypofractionation of photon ACCEPTED MANUSCRIPT radiotherapy was shown to improve local control (LC) and OS in a definitive setting (9, 10) Compared with photons, carbon-ions offer a higher linear energy RI PT transfer (LET) and larger relative biological effectiveness (RBE), and therefore provide a higher probability of tumor control The physical characteristics of carbon-ions, such as the Bragg peak and small lateral SC scattering, are theoretically superior to those of photons in that M AN U carbon-ions can allow a more localized delivery of the radiation dose Definitive carbon-ion radiotherapy (C-ion RT) was adopted by Yanagi et al (11), who reported a 5-year LC rate of 84% in 72 MMHN patients, with a 5-year OS of 27% Therefore, C-ion RT might be a useful and TE D potentially curative option for unresectable tumors In November 2003, following series of clinical trials, the Ministry of Health, Labour and Welfare in xxxx approved C-ion RT as a highly EP advanced medical technology (HAMT) By the end of 2014, there were functional carbon-ion facilities in xxxx (xxxx) We conducted a AC C retrospective multicenter study to assess the clinical outcomes of C-ion RT for head and neck malignancies (xxxx) Herein, we report the results for the subgroup of patients with MMHN Methods and Materials Eligibility ACCEPTED MANUSCRIPT Xxxx was designed as a retrospective multicenter study conducted across carbon-ion facilities in xxxx Patients provided informed consent authorizing the use of their personal information for research RI PT purposes This study was approved by the Institutional Review Boards of each institute and was carried out in accordance with the Declaration of Helsinki This trial is registered with UMIN-CTR SC (http://www.umin.ac.jp/ctr/index-j.htm), identification number xxxx M AN U Patients with head and neck malignancies including ophthalmic tumors who received C-ion RT as an HAMT between November 2003 and December 2014 were included The inclusion criteria were: 1) histologically confirmed malignancy (except choroidal melanoma), 2) TE D no bone or soft tissue tumors, 3) N0 or N1 M0 status, 4) medically inoperable tumors or surgery refusal, 5) definitive intent, 6) measurable tumors, and 7) an Eastern Cooperative Oncology Group EP performance status of 0–2 Patients who previously underwent irradiation for the same lesion were excluded AC C Nine hundred and eight patients were enrolled Of these, 268 patients (excluding choroidal melanoma) had a pathological diagnosis of malignant melanoma The primary sites were the head and neck mucosa in 260 patients, the orbit in 6, and other areas in The latter patients were excluded from the analysis, and the remaining 260 patients with mucosal melanoma were included in the present study ACCEPTED MANUSCRIPT [PD-1] checkpoint inhibitor) have been shown to have complementary activity in melanoma (20, 21) Victor et al demonstrated that radiotherapy acted synergistically with anti-CTLA4 to systemically RI PT enhance melanoma response in a clinical trial; they further demonstrated that the combination of radiation, anti-CTLA-4, and anti-PD-1 ligand promoted tumor response and immunity in vivo (22) SC These reports suggest that C-ion RT with concurrent immunotherapy M AN U might synergistically prolong survival in patients with MMHN In a series of 31 MMHN patients treated with photon therapy, Wada et al (10) reported that fatal complications were observed in patients (6.5%) who received high-dose per fraction radiotherapy In the TE D present study, there were no fatal complications Visual impairment was a common adverse reaction after C-ion RT in patients with MMHN: 10 patients (4%) developed cataracts, which could be surgically EP treated, and only patients (3%) developed irreversible visual impairment Previous studies have reported that the maximum AC C radiation dose administered to the optic nerve is a significant prognostic factor of optic neuropathy, a major cause of irreversible visual impairment, after C-ion RT (23, 24) However, in cases where the tumor invades the orbital space and is close to the optic nerve, it is difficult to reduce the radiation dose to the optic nerve while maintaining the tumor dose In the present study, osteoradionecrosis of the jaw was also a severe adverse reaction In a series of 63 head 15 ACCEPTED MANUSCRIPT and neck tumors treated with C-ion RT, Sasahara et al (25) concluded that the risk factors for osteoradionecrosis of the maxilla included presence of teeth within the PTV and a maxillary volume receiving >50 RI PT Gy (RBE) in a 16-fraction protocol Furthermore, osteoradionecrosis is a result of gingiva regression due to irradiation, leading to an environment that is susceptible to bone infection (26) To reduce the SC risk of osteoradionecrosis of the jaw, extraction of all teeth with a M AN U questionable prognosis within the PTV before commencing C-ion RT and periodical dental management and care after treatment are recommended The present study had several limitations First, it was performed using TE D retrospective data, and several doses and fractionations of C-ion RT were included However, there were no significant differences in tumor control, toxicity, or OS according to dose fractions Since April 2016, an EP integrated treatment schedule using 16 fractions over weeks with a total dose of 57.6 or 64.0 Gy (RBE) has been applied in a multicenter AC C prospective registry study of xxxx Second, there was no consensus on chemotherapy use between the facilities, which might have introduced selection bias because chemotherapy was more commonly administered in patients with a better general condition Third, the median follow-up period was too short to discuss long-term survival after C-ion RT, although 48 patients have survived for >5 years In conclusion, C-ion RT resulted in excellent LC for MMHN with 16 ...ACCEPTED MANUSCRIPT A Multicenter Study of Carbon-Ion Radiotherapy for Mucosal Melanoma of the Head and Neck: Sub-analysis of the Japan Carbon-Ion RI PT Radiotherapy Study Group (J-CROS) Study. .. MANUSCRIPT A Multicenter Study of Carbon-Ion Radiotherapy for Mucosal Melanoma of the Head and Neck: Sub-analysis of the xxxx RI PT Short title: C-ion RT for mucosal melanoma of H&N SC Conflict of interest:... Summary Mucosal melanoma of the head and neck is a rare, radioresistant tumor RI PT This retrospective multicenter study evaluated the effectiveness and safety of carbon-ion radiotherapy for