Retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for T2-4N0 tongue cancer: control of occult neck metastasis

Accepted Manuscript Retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for T2-4N0 tongue cancer: Control of occult neck metastasis Shuhei Minamiyama, DDS, Kenji Mitsudo, DDS, PhD, Yuichiro Hayashi, DDS, Masaki Iida, DDS, PhD, Toshinori Iwai, DDS, Hideyuki Nakashima, DDS, PhD, Senri Oguri, DDS, PhD, Tomomichi Ozawa, DDS, PhD, Toshiyuki Koizumi, DDS, PhD, Makoto Hirota, DDS, PhD, Mitomu Kioi, DDS, PhD, Iwai Tohnai, DDS, PhD PII:

S2212-4403(17)30063-9

DOI:

10.1016/j.oooo.2017.02.004

Reference:

OOOO 1707

To appear in:

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

Received Date: 22 December 2016 Revised Date:

19 January 2017

Accepted Date: 13 February 2017

Please cite this article as: Minamiyama S, Mitsudo K, Hayashi Y, Iida M, Iwai T, Nakashima H, Oguri S, Ozawa T, Koizumi T, Hirota M, Kioi M, Tohnai I, Retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for T2-4N0 tongue cancer: Control of occult neck metastasis, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2017), doi: 10.1016/j.oooo.2017.02.004. 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.

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Retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for T2-4N0 tongue cancer: Control of occult neck metastasis Shuhei Minamiyama, DDS,a,b Kenji Mitsudo, DDS, PhD,a Yuichiro Hayashi, DDS,a Masaki

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Iida, DDS, PhD,a Toshinori Iwai, DDS,a Hideyuki Nakashima, DDS, PhD,a Senri Oguri, DDS, PhD,a Tomomichi Ozawa, DDS, PhD,b Toshiyuki Koizumi, DDS, PhD,a Makoto Hirota, DDS, PhD,a Mitomu Kioi, DDS, PhD,a and Iwai Tohnai, DDS, PhDa

Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate

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a

School of Medicine, 3-9 Fukuura, Kanazawa-Ku, Yokohama, Kanagawa 236-0004, Japan

Department of Dentistry and Oral Surgery, Yamato Municipal Hospital, 8-3-6

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b

Fukami-Nishi, Yamato-City, Kanagawa 242-8602, Japan Corresponding author: Kenji Mitsudo, DDS, PhD Reprint requests: Kenji Mitsudo, DDS, PhD

Department of Oral and Maxillofacial Surgery

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Yokohama City University Graduate School of Medicine 3-9, Fukuura, Kanazawa-Ku, Yokohama, Kanagawa 236-0004 Japan

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E-mail: [email protected] TEL: +81-45-787-2659

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FAX: +81-45-785-8438

Conflict of Interest: None. Word count

abstract: 194 words

complete manuscript word count: 3,855 words number of references: 26 number of figures/tables: 4 figures and 4 tables

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Statement of Clinical Relevance Retrograde superselective intra-arterial chemoradiotherapy for T2-4N0 tongue cancer provided good therapeutic effect for both the primary lesion and occult neck metastasis due to administration to sentinel lymph node via lymphatic canals and perfusion to the neck from

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intra-arterial infusion.

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ABSTRACT Objective. To evaluate the therapeutic results and control of occult neck metastasis in patients with T2-4N0 oral tongue squamous cell carcinoma treated with retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy.

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Study Design. Forty two patients with T2-4N0 tongue cancer (17 with late T2, 13 with T3, and 12 with T4a disease, M0) were treated with intra-arterial chemoradiotherapy. Treatment consisted of retrograde superselective intra-arterial chemotherapy (docetaxel 50-70 mg/m2, cisplatin 125-175 mg/m2) and daily concurrent radiotherapy (50-70 Gy) for 5-7 weeks.

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Results. The median follow-up for all patients was 46.5 (range, 8-105) months. Primary site complete response was achieved in 42 (100%) of 42 cases. Three-year overall survival, progression-free survival, and local control rates were 85.0%, 77.8%, and 91.7%, respectively.

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Delayed neck metastasis was detected in 5 (11.9%) of 42 cases. Grade 3 or 4 toxic changes included oral mucositis in 92.9%, neutrophil count decreased in 21.4%, and platelet count decreased in 4.8%. Grade 3 toxicities included anemia in 16.7%, radiation dermatitis in 9.5%, nausea in 4.8%, and fever in 2.4%.

Conclusions. Retrograde superselective intra-arterial chemotherapy for T2-4N0 tongue neck metastasis.

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cancer provided good overall survival and local control rates, and was effective for occult

Key words: Tongue cancer, Chemoradiotherapy, Retrograde superselective intra-arterial

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infusion, Occult neck metastasis, Organ preservation

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INTRODUCTION Oral tongue cancer is most commonly squamous cell carcinoma (SCC) and associated with a trend toward worse prognosis than cancers of all other oral cavity subsites.1-3 For patients with stage I, II tongue cancer, partial resection of the tongue is the common surgical treatment,

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and dysfunction after surgery is not severe. For patients with locally advanced tongue cancer, extended resection of the tongue including reconstructive surgery causes loss of oral function, including speech, swallowing, and mastication, and reduces quality of life (QOL). To avoid extended surgery for patients with locally advanced oral cancer, we developed retrograde

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superselective intra-arterial chemotherapy and daily concurrent radiotherapy. Previously, we performed definitive retrograde intra-arterial chemoradiotherapy (CRT) for patients with advanced oral cancer, and this treatment is organ-preserving and can minimize functional

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disturbance.4,5

The most important prognostic factor for oral cancer patients is the presence of neck metastasis. A clinically negative neck in patients with early-stage oral cancer (T1-T2N0) including tongue cancer has sometimes resulted in delayed neck metastasis after primary surgery. The frequency of occult neck metastasis is reported to be 25-50% in T2 and 50-58% in T3-4 tongue cancer.6-8 We consider intra-arterial CRT to be effective for the primary lesion

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and occult neck metastasis for patients with T2-4N0 tongue cancer. The aim of the present study was to evaluate the therapeutic results and control of occult neck metastasis in patients with T2-4N0 tongue cancer treated with retrograde superselective

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intra-arterial CRT.

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MATERIALS AND METHODS Patients

Between August 2006 and March 2015, 97 patients with tongue SCC were treated with retrograde superselective intra-arterial CRT. Of these patients, 42 patients (29 male and 13 female; median age 63.5 years; age range, 34-87 years) with late T2 (>3cm), T3, and T4a N0M0 underwent intra-arterial CRT (Table I). All patients were primary cases and had not received previous chemotherapy, radiotherapy, or surgery. The primary lesion and cervical lymph nodes were assessed by enhanced CT, magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT), and ultrasound examination before treatment. N0 criteria of enhanced-CT were minimum axial diameter of node < 10 mm and no 4

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rim enhancement. N0 criteria of PET-CT was SUV < 2.5. N0 criterion of ultrasound was the presence of hilar echoes. TNM staging was classified according to the 2009 Union for International Cancer Control (UICC) staging system.9 The local institutional research board approved this study (No.B141101002), and informed consent was obtained from each

Catheterization via superficial temporal and occipital arteries

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participant. The study was conducted according to the Declaration of Helsinki.

Preoperative 3-dimensional computed tomography angiography (3D-CTA) of the carotid

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artery was performed to identify the main tumor-feeding artery, and determine the morphology of the tumor-feeding artery originating from the external carotid artery.4 If tongue tumor extended to the floor of the mouth and extrinsic muscles of the tongue, two

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catheters were superselectively inserted into the lingual artery (LA) and facial artery (FA), and if the tumor extended to the contralateral side across the median line, another catheter was inserted into the contralateral side LA and/or FA.4,5 Catheterization into the LA or FA was performed via the superficial temporal artery (STA) according to the method described by Tohnai et al.10 and Fuwa et al.11 Catheterization via the occipital artery (OA) was performed

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according to the method described by Iwai et al.12 Perfusion of primary lesion and neck levels

After catheterization, digital subtraction angiography (DSA) and angio-CT were performed to

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check perfusion in all cases. Angio-CT was performed with 6ml diluted contrast medium (3ml iopamidol and 3ml normal saline) for 5 seconds from each inserted catheter to confirm

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perfusion of the primary and neck levels. Neck level was classified according to Som et al.13 Radiotherapy

The patients received external irradiation at a planned total dose of 50-70 Gy/25-35 fractions. The radiotherapy was delivered daily, 5 days per week, using 4 or 6-MV X-rays and a shrinking field technique. The irradiation field for the neck was changed according to primary tumor status (T classification). In cases of T2 disease, the fields contained the primary tumor and levels of I to III of the ipsilateral cervical lymph node area. In cases of T3 and T4a disease, the fields contained the primary tumor and levels of I to III of bilateral cervical lymph node areas. After a total dose of 40 Gy/20 fractions had been delivered to the primary tumor and neck, the portal was reduced to only the primary tumor to spare the spinal cord. 5

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Therefore, the median total doses of primary tumor and neck were 60 Gy (50-70 Gy) and 40 Gy, respectively. The total dose to the spinal cord was restricted to the range from 40 to 45 Gy.

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Superselective intra-arterial chemoradiotherapy

Radiotherapy was performed during the anticancer drug was injected in a bolus infusion for 1 hour via the intra-arterial catheter. Cisplatin (CDDP) was infused 5 mg/m2/day, and the total dose of CDDP was 125-175 mg/m2 (median dose 150 mg/m2). Docetaxel (DOC) was infused

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at 10 mg/m2/week, and the total dose of DOC was 50-70 mg/m2 (median 60 mg/m2) (Figure 1). Sodium thiosulfate (STS) (1 g/m2) was administered intravenously to provide effective

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neutralization after infusion of CDDP.4,5 Assessment and follow-up after treatment

To evaluate treatment, PET-CT, MRI, enhanced CT, and ultrasound examination were performed 4 weeks after completion of intra-arterial CRT. If residual primary tumor was present after this treatment, the policy was to perform a salvage operation 6-8 weeks after the end of intra-arterial CRT. If neck and/or primary recurrence were detected, radical surgery

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was performed as soon as possible. Adverse event assessment

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Adverse events during treatment were evaluated according to the National Cancer Institute – Common Terminology Criteria for Adverse Events version 4.0.

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Statistical analysis

The differences between T classifications in overall survival (OS), progression-free survival (PFS), and local control (LC) rates were analyzed by the log-rank test. Statistical significance was defined as P < .05. All analyses were performed using SPSS ver.20 (IBM, Chicago, IL, USA).

RESULTS Treatment results The median follow-up period was 46.5 months (range, 8-105 months). After retrograde 6

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superselective intra-arterial CRT, primary tumor CR was achieved in 42 cases (100%). Three (7.1%) of 42 cases showed local recurrence during follow-up. Delayed neck metastasis was detected in 5 cases (11.9%): 2 T2, 1 T3, and 2 T4a cases (Table II). In 4 of 5 cases, delayed neck metastasis was observed in the neck area that had no perfusion of anticancer drug. In the

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other case, both the primary lesion and neck showed recurrences, and neck metastasis occurred in the perfusion area of the anticancer drug. Eight patients (19.0%) died: 6 of distant metastasis, 1 of uncontrollable cervical lymph node metastasis, and 1 of non-cancer related causes.

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The Kaplan-Meier method was used to estimate the 3-year OS, PFS, and LC rates, which were 85.0% (95% confidence interval, CI: 73.8-96.2%), 77.8% (95% CI: 64.9-90.7%), and

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91.7% (95% CI: 82.5-100%), respectively (Figure 2). Adverse events

Among the early adverse events, grade 3 or 4 toxic changes included oral mucositis in 39 cases (92.9%), neutrophil count decreased in 9 cases (21.4%), and platelet count decreased in 2 cases (4.8%). Grade 3 toxicities included anemia in 7 cases (16.7%), radiation dermatitis in 4 cases (9.5%), nausea in 2 cases (4.8%), and fever in 1 case (2.4%). Grade 3 dysphagia with

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severe oral mucositis occurred in 35 cases (83.3%). Dysphagia has a tendency to improve within 3 months in most cases. Grade 3 or greater acute kidney injury was not observed. Among late adverse events, grade 3 osteonecrosis of the jaw was observed in 2 cases (4.8%).

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No patients died due to adverse events (Table III). Perfusion of primary lesion and neck levels

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Figure 3 shows flow check DSA, angio-CT and tumor staining after catheterization. The LA was catheterized 54 sides: on the affected side in 38 and on the unaffected side in 16. Levels IA, ipsilateral IB, and contralateral IB were perfused in 28 (51.9%), 40 (74.1%), and 12 (22.2%), respectively (Table IV-a). The FA was catheterized 33 sides: on the affected side in 30 and on the unaffected side in 3. Levels IA, ipsilateral IB, IIA, and contralateral IB were perfused in 22 (66.7%), 32 (97.0%), 5 (15.2%), and 6 (18.2%), respectively (Table IV-b).

DISCUSSION Superselective intra-arterial infusion for head and neck cancer has the advantage of delivering 7

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a high concentration of anticancer drug to the tumor. Lee et al.14,15 reported superselective intra-arterial chemotherapy via the femoral artery by the Seldinger method. Robbins et al.16,17 reported the effectiveness of rapid intra-arterial administration of high-dose CDDP combined with radiotherapy and STS neutralization (RADPLAT). We developed retrograde

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superselective intra-arterial infusion via the STA, and it can be used to provide daily concurrent chemoradiotherapy for patients with advanced oral cancer. We evaluated the therapeutic results and the rate of organ preservation in patients with stage III or IV oral cancer treated with intra-arterial CRT and reported excellent outcomes (5-year OS rate 71.3%,

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LC rate 79.3%).5

Neck recurrence is associated with a poor prognosis in oral cancer.18,19 In particular, tongue cancer is associated with higher rates of occult neck metastases than other oral cancers20,21; its

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frequency is reported to be 25-58% in T2- 4 tongue cancer.6-8 In the present study, delayed neck metastasis was detected in 5 (11.9%) of 42 patients. The following three reasons may explain the lower rate of delayed neck metastasis after superselective intra-arterial CRT. The first reason is irradiation to the neck at least 40Gy according to primary tumor status. The second reason is perfusion of anticancer drug to the neck through the intra-arterial infusion. Previously, some authors reported the treatment effect on the cervical lymph node metastasis

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treated with superselective intra-arterial chemotherapy combined with radiotherapy, and this combination therapy obtained good histopathologic effects on metastatic lymph nodes.22,23 Shah et al.24 reported the prevalence and distribution of neck node metastases for 192 patients

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with N0 oral cavity squamous cell carcinoma after elective radical neck dissections. Occult neck metastasis was present in 65 of the 192 patients (34%). The overall prevalences of nodal metastasis of neck levels I, II, III, IV, and V were 20%, 17%, 9%, 3%, and 0.5%, respectively.

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In the present study, neck levels perfused with retrograde superselective intra-arterial infusion from the LA and FA were levels IA, ipsilateral IB, IIA, and contralateral IB. In addition, a number of cervical lymph nodes of levels I-IIA were perfused from intra-arterial catheter placed in LA/FA (Figure 4). These results suggest that intra-arterial CRT can increase levels of anticancer drug in levels I-IIA and has a therapeutic effect for occult neck metastases in the perfused neck area. As the final reason, intra-arterially injected anticancer drugs passed into sentinel lymph nodes (SLNs) via lymphatic canals. Yokoyama et al.25 reported a translymphatic chemotherapy procedure targeting the SLNs using intra-arterial chemotherapy for oral cancer. Intra-arterial chemotherapy of 50 mg/m2 CDDP was administered either once or twice weekly for patients with tongue cancer, and the patients underwent surgical treatment 8

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including partial resection of the tongue and neck dissection. The mean CDDP concentrations in the SLNs and non-SLNs were 1.2 µg/g and 0.35 µg/g, respectively. Sakashita et al.26 also reported the platinum concentrations of SLNs after preoperative intra-arterial CDDP chemotherapy. Patients with T1-2N0 tongue cancer were treated with preoperative

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intra-arterial chemotherapy to the LA (cisplatin, 100 mg/m2) targeting the primary cancer only, and partial glossectomy together with SLN biopsy and elective neck dissection was performed 2 weeks after intra-arterial chemotherapy. The platinum concentration was higher in the SLNs (0.682 ± 0.246 mg/g) than in the non-SLNs (0.506 ± 0.274 mg/g) (P = .049).

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These results indicate that CDDP administered to primary tongue cancer moves selectively to SLNs via lymphatic canals. Thus, intra-arterial chemotherapy is effective for occult neck metastases due to both administration to SNLs via lymphatic canals and perfusion to the neck

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from the LA/FA.

Three-year LC rates of lateT2, T3, and T4a tongue cancer patients were 100%, 90.0%, and 83.3%, respectively, and there were no significant differences among T classifications. These results indicate that retrograde superselective intra-arterial CRT provided good local control even for locally advanced oral tongue cancer. On the other hand, OS and PFS of T3N0 patients were significantly higher than those of T4aN0 patients (P = .039, .039); 5 of 12

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T4aN0 patients died due to distant metastasis. Patients with T4aN0 tongue cancer may benefit most from additional systemic therapy.

In conclusion, intra-arterial chemotherapy is a method of lymphatic chemotherapy for the

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treatment of occult neck metastasis. Retrograde superselective intra-arterial CRT has a

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therapeutic effect not only for the primary lesion, but also for occult neck metastasis.

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placement via the occipital artery to achieve retrograde superselective intra-arterial chemotherapy for advanced oral cancer: Alternative to approach via the superficial temporal artery. Indian J Otolaryngol Head Neck Surg. 2014;66:205-207. 13. Som PM, Curtin HD, Mancuso AA. Imaging-based nodal classification for evaluation of

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neck metastatic adenopathy. AJR Am J Roentgenol. 2000;174:837-844.

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15. Lee YY, Dimery IW, Van Tassel P, De Pena C, Blacklock JB, Goepfert H. Superselective

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intra-arterial chemotherapy of advanced paranasal sinus tumors. Arch Otolaryngol Head Neck Surg. 1989;115:503-511.

16. Robbins KT, Storniolo AM, Kerber C, et al. Phase I study of highly selective supradose

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cisplatin infusions for advanced head and neck cancer. J Clin Oncol. 1994;12:2113-2120. 17. Robbins KT, Kumar P, Regine WF, et al. Efficacy of targeted supradose cisplatin and concomitant radiation therapy for advanced head and neck cancer: the Memphis experience. Int J Radiat Oncol Biol Phys. 1997;38:263-271.

18. Kowalski LP. Results of salvage treatment of the neck in patients with oral cancer. Arch Otolaryngol Head Neck Surg. 2002;128:58-62.

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19. Ganly I, Goldstein D, Carlson DL, et al. Long-term regional control and survival in patients with "low-risk," early stage oral tongue cancer managed by partial glossectomy and neck dissection without postoperative radiation: the importance of tumor thickness.

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Cancer. 2013;119:1168-1176.

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squamous cell carcinoma of the oral cavity. Cancer. 1997;80:351-356. 21. El-Naaj IA, Leiser Y, Shveis M, Sabo E, Peled M. Incidence of oral cancer occult metastasis and survival of T1-T2N0 oral cancer patients. J Oral Maxillofac Surg. 2011;69:2674-2679.

22. Ikushima I, Korogi Y, Ishii A, et al. Superselective arterial infusion chemotherapy for squamous cell carcinomas of the oral cavity: histopathologic effects on metastatic neck lymph nodes. Eur Arch Otorhinolaryngol. 2007;264:269-275. 23. Uehara M, Shiraishi T, Tobita T, Nonaka M, Asahina I. Antitumor effects on primary tumor and metastatic lymph nodes by superselective intra-arterial concurrent chemoradiotherapy for oral cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 11

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2010;110:172-177. 24. Shah JP, Candela FC, Poddar AK. The patterns of cervical lymph node metastases from squamous carcinoma of the oral cavity. Cancer. 1990;66:109-113. 25. Yokoyama J, Ito S, Ohba S, Fujimaki M, Ikeda K. A novel approach to translymphatic

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26. Sakashita T, Homma A, Oridate N, et al. Platinum concentration in sentinel lymph nodes after preoperative intra-arterial cisplatin chemotherapy targeting primary tongue cancer.

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Acta Otolaryngol. 2012;132:1121-1125.

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FIGURE LEGENDS Fig. 1. Treatment schedule. Treatment consisted of retrograde superselective intra-arterial chemotherapy (docetaxel 60 mg/m2, cisplatin 150 mg/m2) and daily concurrent radiotherapy

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(60 Gy) for 6 weeks. Fig. 2. Overall survival (A), progression-free survival (B), and local control (C). Three and 5-year OS rates are 85.0 and 78.5%, respectively. At 3 years, the OS rates of T2N0, T3N0, and T4aN0 patients are 94.1%, 100.0%, and 56.3%, respectively. The OS of T3N0 patients is

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significantly higher than that of T4aN0 patients (P = .039) (A).

Three and 5-year PFS rates are 77.8% and 74.5%, respectively. At 3 years, the PFS rates of T2N0, T3N0, and T4aN0 patients are 82.4%, 90.0%, and 58.3%, respectively. The PFS of

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T3N0 patients is significantly higher than that of T4aN0 patients (P = .039) (B). Three and 5-year LC rates are both 91.7%. At 3 years, the LC rates of T2N0, T3N0, and T4aN0 patients are 100.0%, 90.0%, and 83.3%, respectively. No significant difference is observed in the LC among the different T patients (C). Abbreviations

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OS = overall survival, PFS = progression-free survival, LC = local control Fig. 3. Perfusion check in squamous cell carcinoma of the right tongue (T3N0M0). Two catheters were superselectively inserted into the right lingual artery via the occipital artery (A:

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OA-LA) and the right facial artery via the superficial temporal artery (B: STA-FA). The tumor stain of the right tongue is seen on the DSA (A: OA-LA: arrow). Tumor staining of the right tongue from the right LA (C: arrowhead) and the right floor of the mouth from the right FA

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(D: arrowhead) can be seen with the use of contrast medium. Neck levels IA and right IB are perfused from right LA (C), and neck levels IA and right IB are perfused from right FA (D). The staining by injection of indigotindisulfonate sodium from the right LA is visible to the right side of the tongue, however, the staining is not visible on the floor of the mouth (E: arrowhead). The staining of the floor of the mouth and lower gingiva is seen from the right FA (F: arrowhead). Abbreviations DSA = digital subtraction angiography, LA = lingual artery, FA = facial artery, OA = occipital artery, STA = superficial temporal artery

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Fig. 4. Perfusion of cervical lymph nodes from catheters inserted into the lingual and facial arteries. Case 1: Left tongue cancer (T3N0). Small lymph node is observed in neck level IA before treatment (A: arrowhead). Perfusion from the left LA is observed in neck level IA and ipsilateral level IB, and level IA lymph node is enhanced (B: arrowhead). Case 2: Right

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tongue cancer (Late T2N0). Small lymph nodes are observed in bilateral neck level IB before treatment (C: arrowheads). Perfusion from the right LA is observed in neck level IA and bilateral level IB, and bilateral level IB lymph nodes are enhanced (D: arrowheads). Case 3: Right tongue cancer (Late T2N0). Lymph node is observed in right neck level IIA before

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treatment (E: arrowhead). Perfusion from the right FA is observed in ipsilateral level IB and IIA, and the ipsilateral level IIA lymph node is enhanced (F: arrowhead). LA = lingual artery, FA = facial artery

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Abbreviations

Table I. Patients’ characteristics (N=42)

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Table II. Cases of delayed neck metastasis

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Table III. Adverse events (NCI-CTCAE v.4.0)

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Table IV. Perfusion of neck levels from catheters

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Table I

Patients’ characteristics (N=42)

Characteristics

n or median

(% or range)

Age (y)

63.5

(34-87)

Male

29

(69)

Female

13

(31)

T2 (late T2)

17

(40)

T3

13

(31)

T4a

12

(29)

II

17

(40)

III

13

IV

12

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Stage classification

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T classification

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Gender

(31)

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(29)

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Table II Cases of delayed neck metastasis Age(y)/Gender

T classification

Site

Period(m)

Perfusion

Local recurrence

1

68/F

T4a

ipsilateral IIA

4

-

-

3

67/M

T2 (late T2)

ipsilateral VB

8

-

-

10

74/F

T3

ipsilateral IB

34

+

+

16

68/M

T2 (late T2)

ipsilateral IIA, IIB

7

-

-

18

69/M

T4a

ipsilateral III

4

-

+

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No.

Period(m), The period (months) until delayed neck metastasis occurred; Perfusion, Perfusion of

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anticancer drug at neck level with delayed neck metastasis

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Table III Adverse events (NCI-CTCAE v.4.0) Toxicity

Grade [n (%)] 2

3

4

Neutrophil count decreased

15 (36)

18 (43)

7 (17)

2 (5)

Anemia

11 (26)

24 (56)

7 (17)

0

Platelet count decreased

26 (62)

1 (2)

1 (2)

Nausea

31 (74)

9 (21)

2 (5)

Oral mucositis

0

3 (7)

38 (90)

Radiation dermatitis

13 (31)

25 (60)

4 (10)

Dysphagia

1 (2)

6 (14)

35 (83)

0

Acute kidney injury

4 (10)

4 (10)

0

0

Fever

16 (38)

Osteonecrosis of the jaw

1 (2)

RI PT

1

1 (2)

-

1 (2)

M AN U

SC

0

8 (19)

1 (2)

0

3 (7)

2 (5)

0

AC C

EP

TE D

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0

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Table IV Analysis of the perfusion area from the catheter (a) Perfusion of neck levels from the catheter inserted into the LA ipsilateral IA

IB

IIA

IIB-V

IB

IIA

IIB-V

28

40

0

0

12

0

0

(51.9%)

(74.1%)

(22.2%)

LA, lingual artery. (b) Perfusion of neck levels from the catheter inserted into the FA

IA

IB

IIA

IIB-V

22

32

5

0

(66.7%)

(97.0%)

(15.2%)

AC C

EP

TE D

FA, facial artery.

IB

IIA

IIB-V

6

0

0

M AN U

n = 33

contralateral

SC

ipsilateral

RI PT

n = 54

contralateral

(18.2%)

AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

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