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)

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[.]

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)

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.

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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)

Short title: C-ion RT for mucosal melanoma of H&N

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∗

† 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

Corresponding author: Masashi Koto, Hospital of the National Institute

of Radiological Sciences, National Institutes for Quantum and

Radiological Sciences and Technology 4-9-1 Anagawa, Inage-ku

263-8555 Chiba, Japan Tel: +81-43-206-3360; Fax:

+81-43-256-6506; E-mail: koto.masashi@qst.go.jp

Conflict of interest: none

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

A Multicenter Study of Carbon-Ion Radiotherapy for Mucosal Melanoma

of the Head and Neck: Sub-analysis of the xxxx

Short title: C-ion RT for mucosal melanoma of H&N

Conflict of interest: None

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

Methods and Materials: MMHN patients with N0-1M0 status who were treated with C-ion RT at 4 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 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 patients had T3 tumors, 147 had T4a tumors, and 27 had T4b tumors Two hundred and fifty-one patients were diagnosed with N0 disease, and 9 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

No patients developed Grade 5 late morbidities

Conclusion: C-ion RT is a promising treatment option for MMHN

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 Sweden, between 1960 and 2000, the incidence of MMHN increased significantly (6)

MMHN is typically aggressive, resulting in poor prognosis In the Surveillance, Epidemiology, and End Results registry, Jethanamest et

al (7) reported that between 1973 and 2007, the 5-year overall

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

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 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 advanced medical technology (HAMT) By the end of 2014, there were

4 functional carbon-ion facilities in xxxx (xxxx) We conducted a 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

of each institute and was carried out in accordance with the

Declaration of Helsinki This trial is registered with UMIN-CTR

(http://www.umin.ac.jp/ctr/index-j.htm), identification number xxxx 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)

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 performance status of 0–2 Patients who previously underwent

irradiation for the same lesion were excluded

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 2 The latter

8 patients were excluded from the analysis, and the remaining 260 patients with mucosal melanoma were included in the present study

Evaluation of clinical outcome

LC was defined as no evidence of tumor regrowth in the planning target volume (PTV) Regional control was defined as no evidence of regional lymph node recurrence or head and neck mucosa skip lesions outside the PTV In normal tissues, acute and late reactions after C-ion

RT were re-classified according to the National Cancer Institute

Common Terminology Criteria for Adverse Events, version 4.0

Statistical analyses

All survival times were calculated from the first day of C-ion RT LC, OS, and progression-free survival (PFS) rates were determined using the Kaplan–Meier method For univariate analyses, log-rank tests were used to compare LC and OS among the subgroups All factors with statistically significant associations in the univariate analysis were included in a multivariate analysis using the Cox proportional hazards model The effect of concurrent chemotherapy on developing mucositis was assessed with the chi-square test A p-value < 0.05 was

considered statistically significant, and all statistical tests were

two-sided Statistical analyses were performed using SPSS software, version 23 (IBM Corp., Armonk, NY, USA)

Results

Treatment characteristics

Carbon-ion doses are expressed as photon-equivalent doses in grays (Gy) (RBE) (13), and were defined as the physical dose multiplied by the carbon-ion RBE The biological flatness of the spread-out Bragg peak (SOBP) was normalized using the surviving fraction of human salivary gland tumor cells at the distal SOBP region, resulting in a carbon-ion RBE of 3

Patients were positioned in customized cradles and immobilized using low-temperature thermoplastic shells Magnetic resonance imaging and endoscopic findings were routinely performed for the

determination of the gross tumor volume (GTV) The clinical target volume (CTV) included whole anatomical sites where the tumors were located To spare organs at risk, a shrinking-field technique with boost was used The PTV had margins of 2–5 mm added around the CTV A median of 5 ports were used to improve dose distribution The target reference point dose was defined as the isocenter, and an isodose line

representing 90% of the reference point dose encompassed the PTV

No patients underwent prophylactic neck irradiation During each treatment session, the patient’s position was verified with a

computer-aided online positioning system The patient was positioned

on the treatment couch using immobilization devices, and then digital orthogonal radiographic images were taken and transferred to the positioning computer The positioning images were compared with the reference images digitally reconstructed from CT scans If the

difference in positioning was more than 2 mm, the treatment couch was repositioned until the desired position was achieved

Treatment characteristics for C-ion RT for all patients are shown in Table 2 Schedule selection was dependent on institution, not on patient The most commonly prescribed dose was 57.6 Gy (RBE) in 16 fractions with 4 fractions per week

Chemotherapy including dimethyl traizeno imidazole carboxamide (DTIC) was administered to 155 patients (60%) Of the 155 patients,

129 patients (50%) were administered both one cycle of concurrent chemotherapy and several cycles of adjuvant chemotherapy consisting

of DTIC (120 mg/m2, day 1–5), nimustine hydrochloride (70 mg/m2, day 1), and vincristine (0.7 mg/m2, day 1) in 4-week intervals The other 26 patients (10%) sequentially received the same or different chemotherapy regimens, including DTIC

Local control and survival

The median follow-up period was 22 months (range, 1–132 months) Thirty-eight patients (15%) developed local recurrence Of these, 31 (12%) developed recurrences at the center of the PTV and 7 (3%) at the margin of the PTV The 2-year and 5-year LC rates were 83.9% (95% confidence interval [CI], 78.2–89.6) and 72.3% (95% CI, 63.7–80.9), respectively (Figure 1)

On the last follow-up date, 102 patients (39%) had died of their disease and 4 (2%) had died of unrelated causes The initial recurrence patterns in the 159 patients (61%) who developed recurrences were distant metastases in 96 patients (37%), regional recurrence in 32 (12%), local recurrence in 24 (9%), and regional + distant metastases

in 7 (3%) The 2- and 5-year OS rates were 69.4% (95% CI, 63.1–75.7) and 44.6% (95% CI, 36.8–52.4), respectively (Figure 2)

Forty-eight patients survived for >5 years The 2- and 5-year PFS rates were 40.4% (95% CI, 33.9–46.9) and 27.2% (95% CI, 20.7–33.7), respectively (Figure 2)

Prognostic factors

The results of univariate and multivariate analyses of prognostic factors for LC and OS are shown in Table 3 Univariate analysis did not reveal any significant prognostic factors for LC However, a small gross tumor volume (<25.4 cc) (p = 0.009) and concurrent chemotherapy

Acute and late toxicities of normal tissues

With regard to C-ion RT-related acute toxicity (Grade ≥3), Grade 3 mucositis was observed in 49 patients (19%) and Grade 3 dermatitis was noted in 5 (2%) There were no Grade 4 toxicities In terms of chemotherapeutic toxicities, 22 patients (8%) developed Grade ≥3 hematological toxicities and 3 (1%) developed Grade 3 liver

dysfunction The frequencies of Grade 3 mucositis were 25% and 13%

in patients who did or did not undergo concurrent chemotherapy, respectively There was a significant difference between these

mucositis frequencies (p = 0.015) However, all patients experiencing mucositis were able to successfully complete C-ion RT

A total of 34 Grade ≥3 late toxicities were observed in 33 patients (13%) (Table 4) With regard to visual function, 5 patients (2%) developed ipsilateral blindness (Grade 4) and 13 (5%) developed Grade 3 visual impairment The causes of blindness were optic

31 MMHN patients who underwent definitive photon radiotherapy Over a median follow-up period of 16 months, local recurrence was observed in 13 (41.9%) patients, and the 3-year cause-specific

survival rate was 33%

The present study was a large multicenter retrospective study that included patients who underwent C-ion RT Compared with historical data of photon radiotherapy, C-ion RT achieved superior LC and

showed a notable survival benefit The data were comparable to

previously reported survival data following surgery (8), although 66%

of the patients had inoperable tumors Complete surgical resection with clear margins is the mainstay of MMHN management; however, previous studies have reported postsurgery LC rates of <50% (14, 15) Because the extent of histopathologically assessed tumor spread is usually greater than the extent of gross disease, it is not easy to achieve a free surgical margin while preserving vital structures Lee et

al (15) reported that local failure was associated with a significantly increased rate of distant metastasis and poor OS Penel et al (16) demonstrated that MMHN patients with positive surgical margins showed a 21-fold increased risk of death In C-ion RT planning for MMHN, a wider treatment margin to cover microscopic lesions is

applied, unlike the approach used for other head and neck tumors In the present study, local recurrences at the margin of the PTV occurred

in only 7 patients (3%), although 31 patients (12%) developed local recurrence at the center of the PTV Consequently, the 2-year LC rate was 83.9% This excellent LC probably contributed to the favorable 2-year OS rate (69.4%)

In the present study, small gross tumor volume and concurrent

chemotherapy including DTIC were independent prognostic factors for good OS, although these were not prognostic factors for LC Thus, these factors might contribute to the development of distant

metastasis Moreover, an effective cytotoxic chemotherapy regimen for MMHN has not yet been established In the present study, cytotoxic drugs including DTIC, a key treatment for cutaneous melanoma, were used, and patients who underwent concurrent chemotherapy had significantly superior OS rates compared to those who did not

However, in a previous study involving DTIC treatment, a long-term complete response was noted in only 1–2% of patients (19) The definitive reason for the significant improvement in outcomes achieved with DTIC in the present study is unclear; however, the combination of C-ion RT with concurrent chemotherapy including DTIC could be a viable treatment option for MMHN

Recently, ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA4] checkpoint inhibitor) and nivolumab (a programmed death 1