Int. J. Oral Maxillofac. Surg. 2017; 46: 682–686 http://dx.doi.org/10.1016/j.ijom.2017.01.011, available online at http://www.sciencedirect.com

Clinical Paper Head and Neck Oncology

S. Sugiyama, T. Iwai, S. Oguri, Facial nerve paralysis after T. Koizumi, K. Mitsudo, I. Tohnai Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of super-selective intra-arterial Medicine, Yokohama, Kanagawa, Japan chemotherapy for oral cancer

S. Sugiyama, T. Iwai, S. Oguri, T. Koizumi, K. Mitsudo, I. Tohnai: Facial nerve paralysis after super-selective intra-arterial chemotherapy for oral cancer. Int. J. Oral Maxillofac. Surg. 2017; 46: 682–686. # 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Abstract. Facial nerve paralysis (FNP) after super-selective intra-arterial chemotherapy (SSIAC) is a relatively rare local side effect of SSIAC to the maxillary (MA) or the (MMA). The incidence and prognosis of FNP after SSIAC in 381 patients with oral cancer (133 with catheterization of the MA, 248 without) was investigated retrospectively. Only three patients (two male and one female) had FNP, for an incidence of 0.8%. All patients with FNP had undergone catheterization of the MA, and the incidence of FNP in this group was 2.3% (3/133). One of the three patients with FNP had paralysis of the third branch of the trigeminal nerve. FNP occurred a mean of 8.7 days (range 5–11 days) after initial SSIAC, and the mean total dose of cisplatin was 55.8 mg (range 42.5–67.2 mg) and of docetaxel was 25.4 mg (range 17.0–33.6 mg). Key words: facial nerve paralysis; intra-arterial chemotherapy; super-selective intra-arterial FNP resolved completely a mean of 12.7 months (range 6–19 months) after onset. chemotherapy; oral cancer; complication. Because the administration of anticancer agents via the MA or MMA carries a risk of FNP, this information will be useful when obtaining informed consent from Accepted for publication 16 January 2017 patients before treatment. Available online 10 February 2017

Intra-arterial chemotherapy (IAC) has mour-feeding with highly con- Materials and methods been used to treat head and neck cancer centrated anticancer agents may induce This study included 381 patients with oral since the 1950s1–3; however, the efficacy local side effects in vital tissues or organs 1 cancer who underwent retrograde SSIAC of early IAC was unproven. Recently, that receive a blood supply from those and daily concurrent radiotherapy at the progress in vascular radiological techni- arteries. Cranial nerve damage, in partic- authors’ institution between June 2006 ques has led to the development of super- ular facial nerve paralysis (FNP), is a and May 2016. Of the 381 patients, 133 selective IAC (SSIAC), which has the relatively rare local side effect of IAC underwent catheterization of the MA and advantage of delivering a higher concen- or SSIAC to the (MA) or 248 underwent catheterization of arteries tration of anticancer agents to the tumour middle meningeal artery (MMA).3,7 The other than the MA. The incidence of FNP bed than IAC; SSIAC has been applied to purpose of this study was to investigate after SSIAC with respect to sex, age, head and neck cancers, including oral the incidence and prognosis of FNP after primary tumour site, catheter tip position, cancers.1–8 However, the infusion of tu- SSIAC. anticancer agent, and additional cranial

0901-5027/060682 + 05 # 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. [(Fig._1)TD$IG] FNP after super-selective chemotherapy 683

Infusor, 7-day type; Baxter, Chicago, IL, USA). The anticancer agents were injected for 1 h in a bolus through the intra-arterial catheter when radiotherapy was performed. The dose of cisplatin was 5 mg/m2/day[2_TD$IF] and of docetaxel was 10 mg/ m2/week, and SSIAC was performed for 4–7 weeks. Sodium thiosulphate (1 g/m2) was administered intravenously to provide effective neutralization after cisplatin ad- ministration. Conventional radiotherapy was performed at 4 or 6 MV and the total dose delivered to the primary tumour was 40–70 Gy (2 Gy/fraction/day).

Results Among 381 patients with oral cancer who underwent SSIAC, only three (two male and one female) had FNP (Table 1), for an incidence of 0.8%. All patients with FNP had undergone catheterization of the MA, and the incidence of FNP in this group was 2.3% (3/133). There were no patients with FNP among the 248 with catheterization of arteries other than the MA. One of the three patients with FNP had paralysis of the third branch of the trigeminal nerve. FNP occurred a mean of 8.7 days (range Fig. 1. Super-selective intra-arterial catheterization via the superficial temporal artery and 5–11 days) after initial SSIAC, and the . mean total dose of cisplatin was 55.8 mg (range 42.5–67.2 mg) and of docetaxel nerve paralysis, as well as the onset and et al.9 (Fig. 1). A hook-shaped catheter was 25.4 mg (range 17.0–33.6 mg). All recovery of FNP after SSIAC, was inves- (Medikit Co., Ltd, Tokyo, Japan) was patients with FNP were treated immedi- tigated retrospectively. super-selectively inserted into the target ately with an intravenous administration artery and fixed to the skin. When cathe- of steroid, and the FNP had resolved terization using a hook-shaped catheter completely at a mean of 12.7 months Retrograde super-selective intra-arterial was not stable, the guide wire exchange (range 6–19 months) after onset. chemoradiotherapy method was used to replace it with a Catheterization via the superficial tempo- Anthron P-U catheter (Toray Medical Discussion ral artery was performed according to the Co., Ltd, Tokyo, Japan). Heparinized sa- method described by Tohnai et al.6 and line (100 units/ml) with 10 mg predniso- Although FNP after IAC for head and neck catheterization via the occipital artery was lone was administered continuously into cancer is relatively rare,2,3,7,10–13 the performed according to the method of Iwai the catheter via an infusion pump (Baxter blood supply of the facial nerve (FN) is

Table 1. Reported cases of facial nerve paralysis after (super-selective) intra-arterial chemotherapy. Sex/ Primary Catheter tip Anticancer agent Onset after Additional Recovery Case No. (Ref.) age tumour site position (total dose) initial infusion paralysis (month) 1(10) NA NA ECA CDDP (100 mg/m2  1) 3 days None CR (0.5) 2(2) 70/F Nasopharynx ECA CDDP (20 mg/day  8)a 10 days None None (NA) 3(8) 63/F Parotid gland PAA CDDP (100 mg/m2/week  6) NA None None (60) 4(3) 60/M Maxillary sinus MMA CDDP (100 mg/m2  1) 3 days V2 None (12) 5(3) 71/M Maxillary sinus MMA CDDP (100 mg/m2  1) 5 days None CR (6) 6(7) NA Maxillary sinus MA CDDP (20–50 mg/m2  3) 2 weeks None CR (30) 7 (Present study) 62/M Upper gingiva MA CDDP (5 mg/m2/day  5) 5 days V3 CR (6) DOC (10 mg/m2/week  1) 8 (Present study) 78/F Upper gingiva MA CDDP (5 mg/m2/day  9) 11 days None CR (13) DOC (10 mg/m2/week  2) 9 (Present study) 82/M Buccal mucosa MA CDDP (5 mg/m2/day  8) 10 days None CR (19) DOC (10 mg/m2/week  2) CDDP, cisplatin; CR, complete recovery; DOC, docetaxel; ECA, ; F, female; M, male; MA, maxillary artery; MMA, middle meningeal artery; NA, not available; PAA, posterior auricular; V2, second branch of the trigeminal nerve; V3, third branch of the trigeminal nerve. a Continuous infusion. [(Fig._2)TD$IG]684 Sugiyama et al.

stem vessel that divides laterally into the petrosal artery and medially into a branch to the trigeminal ganglion.14 The petrosal artery is sometimes double, with the sec- ond vessel arising from the common trunk or the accessory meningeal artery.14 The accessory meningeal artery originates from the MMA in 47–75% of individuals, from the MA in 25–47%, and from both in 0–6%.16,17 Among the three patients with FNP in the present study, the accessory meningeal artery originated from the MMA in two patients (67%) and from the MA in one patient (33%). The incidence of FNP has been reported previously in the English-language litera- ture as being 1.6–10% (Table 2). Although conventional IAC—which places the cath- eter tip in the external carotid artery— provides a lower dose of anticancer agents to the feeding artery of the FN compared with SSIAC, FNP has still been reported in such cases.2,10–13 Because low-dose anti- cancer agents are administered daily in the present authors’ method of SSIAC, the dose of anticancer agents to target arteries may be similar to high-dose IAC. The incidence of FNP in the present study (0.8% in 381 patients) is lower than that in other reports, and no FNP was observed Fig. 2. Schematic diagram of the external carotid artery and its branches (AMA, accessory in patients without catheterization of the meningeal artery; ECA, external carotid artery; IAA, ; MA, maxillary MA; however, the incidence of FNP in artery; MMA, middle meningeal artery; OA, occipital artery; PA, petrosal artery; PAA, posterior auricular artery; SA, stylomastoid artery; STA, superficial temporal artery; V, trigeminal nerve; patients with catheterization of the MA VII, facial nerve.). was 2.3% (3/133). Takanami et al. ana- lyzed the relationship between the position of the catheter tip and the incidence of FNP after high-dose SSIAC.3 Of 20 important in considering the mechanism branches from the internal auditory ar- patients with head and neck cancer, three of FNP after IAC. The intratemporal seg- tery.14 In the facial canal, the FN is sup- underwent catheterization of the MA and ments of the FN are supplied by several plied by the petrosal artery, which is a five underwent catheterization of the sources: the internal auditory artery, sty- branch of the MMA, and the stylomastoid MMA. Although there was no FNP in lomastoid artery, petrosal artery, and a artery, which is a branch of the posterior patients with catheterization of the MA, branch of the .14,15 auricular artery or the occipital artery two patients with catheterization of the In the auditory canal, the FN is supplied by (Fig. 2).14 The MMA gives off a short MMA had FNP, for an incidence of

Table 2. Incidence of facial nerve paralysis after (super-selective) intra-arterial chemotherapy. Author (Ref.) Incidence of FNP Primary tumour site Catheter tip position Anticancer agent (dose) Frustaci et al.2 1.6% (1/63) Head and neck cancer ECA CDDP (20 mg/day)a Mortimer et al.10 4% (1/25) Head and neck cancer ECA CDDP (100 mg/m2) Claudio et al.11 5% (2/40) Head and neck cancer ECA Vincristine (1.5 mg/week), bleomycin (45 mg/week), MTX (20 mg/week) Cruz et al.12 9.1% (4/44) Head and neck cancer ECA 5-FU (15 mg/kg/day), MTX (5 mg/day), vinblastine (0.02 mg/kg/day) Damascelli et al.13 10% (6/60) Head and neck cancer ECA, its branches Paclitaxelb (150–230 mg/m2) Takanami et al.3 10% (2/20) Head and neck cancer MMA, MA, ECA, others CDDP (100 mg/m2) Kaneko et al.7 2.8% (1/36) Maxillary sinus MA, ECA CDDP (20–50 mg/m2) Present study 0.8% (3/381) Oral cancer MA, FA, LA, ECA, others CDDP (5 mg/m2/day), DOC (10 mg/m2/ 2.3% (3/133) Gingiva, hard palate, MA week) buccal mucosa 5-FU, fluorouracil; CDDP, cisplatin; DOC, docetaxel; ECA, external carotid artery; FA, ; FNP, facial nerve paralysis; LA, ; MA, maxillary artery; MMA, middle meningeal artery; MTX, methotrexate. a Continuous infusion. b Paclitaxel-charged human albumin nanoparticles. FNP after super-selective chemotherapy 685

40% (2/5). Considering the blood supply According to de Vries et al., FNP after tery in maxillary cancer. Auris Nasus Larynx of the FN, the risk of FNP after SSIAC embolization of the MMA, MA, occipital 2009;36:479–81. may increase when the position of the artery, and their branches—including the 4. Mitsudo K, Koizumi T, Iida M, Iwai T, catheter tip is closer to the feeding artery.3 stylomastoid artery or petrosal artery, Nakashima H, Oguri S, et al. Retrograde Through a search of the English-lan- which is the feeding artery of the FN— superselective intra-arterial chemotherapy guage literature, six well-described cases is not commonly reversible.19 In some and daily concurrent radiotherapy for stage of FNP after IAC or SSIAC were identi- patients, FNP is accompanied by trigemi- III and IVoral cancer: analysis of therapeutic fied. These reported cases of FNP, along nal nerve paralysis caused by an obstruc- results in 112 cases. Radiother Oncol with the three cases in the present study, tion in the accessory meningeal artery, 2014;111:306–10. 5. Fuwa N, Kodaira T, Furutani K, Tachibana were reviewed with regard to sex, age, which supplies a portion of the trigeminal H, Nakamura T, Nakahara R, et al. Intra- primary tumour site, catheter tip position, nerve and ganglion.19 In contrast, previous arterial chemoradiotherapy for locally ad- anticancer agent, additional cranial nerve studies have suggested that FNP caused by vanced oral cavity cancer: analysis of thera- paralysis, and onset and recovery of FNP inflammation after IAC or 10–12 peutic results in 134 cases. Br J Cancer (Table 1). The catheter tip was placed in SSIAC is usually mild and reversible, 2008;98:1039–45. the MMA, MA, posterior auricular artery, taking several days to resolve. Because of 6. Tohnai I, Fuwa N, Hayashi Y, Kaneko R, or external carotid artery, all of which the vascular anatomy of the FN tract, the Tomaru Y, Hibino Y, et al. New superselec- supply blood to the FN from branches horizontal segment of the intratemporal tive intra-arterial infusion via superficial including the petrosal artery or stylomas- FN is considered to be the most vulnerable temporal artery for cancer of the tongue toid artery. Although cisplatin was admin- to damage by oedema, as the FN occupies and tumor tissue platinum concentration af- istered in all well-described cases of FNP almost the entire intracranial space and ter carboplatin (CBDCA) infusion. Oral after IAC or SSIAC (Table 1),2,3,7,8,10 FNP could become ischemic if intracranial Oncol 1998;34:387–90. after IAC or SSIAC may also be caused by pressure increases.16[3_TD$IF]Blood flow to this 7. Kaneko T, Tada Y, Maruya S, Takeishi E, the administration of other anticancer portion is supplied by the petrosal artery, Miura K, Masubuchi T, et al. Intra-arterial agents such as fluorouracil, methotrexate, the terminal branch of the MMA. When chemoradiation therapy with weekly low- bleomycin, vinblastine, vincristine, doce- SSIAC is performed for head and neck dose cisplatin for squamous cell carcinoma taxel, and paclitaxel-charged human albu- cancer, including oral cancer, the admin- of the maxillary sinus. Int J Oral Maxillofac min nanoparticles (Table 2).11–13,18 istration of anticancer agents via the MA Surg 2015;44:697–704. Because FNP has been shown to occur or MMA carries a risk of FNP. The infor- 8. Kashiwagi N, Fujii T, Nishiyama K, Naka- after IAC as well as after SSIAC, and with mation presented herein regarding this risk nishi K, Tomiyama N, Yagyu Y, et al. Super- selective intra-arterial chemotherapy with the administration of various doses of will be useful when obtaining informed concurrent radiotherapy for advanced parot- anticancer agents to the tumour-feeding consent from patients before treatment. id squamous cell carcinoma: a case report. artery, the type or dose of anticancer agent Jpn J Clin Oncol 2015;45:378–80. administered is unlikely to be associated Funding 9. Iwai T, Fuwa N, Hirota M, Mitsudo K, with the incidence of FNP. On the other Tohnai I. Secure surgical method for catheter hand, the catheter tip position appears to No funding. placement via the occipital artery to achieve be important in determining the occur- retrograde superselective intra-arterial che- rence of FNP, considering the blood sup- motherapy for advanced oral cancer: alter- ply of the FN. The onset of FNP after Competing interests native to approach via the superficial the initial infusion of anticancer agents No conflict of interest. temporal artery. 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