Treatment results of continuous intra-arterial CBDCA infusionchemotherapy in combination with radiation therapy forlocally advanced tongue cancerNobukazu Fuwa, MD,a Takeshi Kodaira, MD,a Kazuhisa Furutani, MD,b

Hiroyuki Tachibana, MD,a Tatsuya Nakamura, MD,a Nagoya, JapanAICHI CANCER CENTER AND SHIZUOKA CANCER CENTER

Objective: The objective of this study was to improve the treatment results for locally advanced tongue cancer. Acombination of radiotherapy with continuous intra-arterial therapy using CBDCA was used.Study design: According to TNM staging (1997), 29 patients had stage III lesions and 11 patients had stage IV (M0)lesions. A catheter was inserted through the lingual artery in 26 patients, through the external carotid artery in 11patients, and through the faciolingual trunk in 2 patients. CBDCA was continuously infused for 4 to 6 weeks. With IAchemotherapy, external irradiation (median dose: 46.8 Gy) was simultaneously performed, and 1 to 2 courses ofsystemic chemotherapy were performed in 19 patients before intra-arterial chemotherapy.Results: The 5-year local control rate was 65%. The 5-year OS rate was 39.5%. There were no clinically significantadverse side effects.Conclusion: Continuous IA CBDCA and concurrent radiation therapy can be delivered safely with good efficacy for

locally advanced carcinoma of the tongue. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:714-9)

In 1950, Klopp and Alfordd initially reported arterialinjection therapy for head and neck cancer.1 Thereafter,there were 2 innovations: the development of a proce-dure for selective arterial injection,2-5 and arterial in-jection therapy with high-dose cisplatin (CDDP) in-volving the neutralization of CDDP with sodiumthiosulfate (STS), as described by Robbins et al.2,3 Inthe 1990s, arterial injection therapy was reevaluated asa new treatment option for head and neck cancer.

Selective arterial injection therapy for head and neckcancer is classified into 2 types: selective arterial injec-tion through the femoral artery by Seldginger’s meth-od,2-5 and an approach through the superficial temporalartery.6,7 The former procedure is relatively simple, anda catheter can be inserted into several arteries. How-ever, anticancer agents must be administered in a shortduration, and catheter operations may lead to cerebraltransfer of a thrombus, causing cranial nerve disordersin 2% to 5% of patients. The latter procedure is slightlycomplex; however, administration of anticancer agents

The authors indicate no potential conflicts of interest.aDepartment of Radiation Oncology, Aichi Cancer Center Hospital,Nagoya, Japan.bDepartment of Radiation Oncology, Shizuoka Cancer Center.Received for publication Jun 20, 2007; returned for revision Oct 24,2007; accepted for publication Nov 21, 2007.1079-2104/$ - see front matter© 2008 Mosby, Inc. All rights reserved.

doi:10.1016/j.tripleo.2007.11.023

714

over a long duration is possible, and there is no risk ofcranial nerve disorders.

In 1992, we started chemoradiation therapy, in whichradiotherapy was combined with continuous arterialinjection therapy with carboplatin (CBDCA), using thelatter procedure in advanced oral/maxillary cancer pa-tients in whom surgery was impossible or those whorefused surgery. In particular, patients with tongue can-cer or tongue root cancer responded well to this ther-apy, suggesting its usefulness in patients with locallyadvanced tongue cancer.8-10 In this study, we retrospec-tively investigated the results of treatment in patientswith stage III/IV tongue cancer to examine the signif-icance and limitations of this therapy.

MATERIALS AND METHODS

MaterialsThe subjects were 40 patients with locally advanced

tongue cancer who underwent continuous CBDCA ar-terial injection therapy combined with radiation therapybetween January 1993 and August 2002 (Table I). Agesranged from 25 to 87 years, with a median of 68 years.There were 26 males and 14 females. The performancestatus (PS) was evaluated as 0 or 1 in 31 patients, 2 in8 patients, and 3 in 1 patient. According to the TNMstaging (1997),11 29 patients had stage III lesions, and11 patients had stage IV (M0) lesions. In all patients,the histopathological type was squamous cell carci-noma. This therapy was performed for the following

reasons: 19 patients refused surgery, age or a poor PS

OOOOEVolume 105, Number 6 Fuwa et al. 715

score was considered in 18 patients, and surgery wasconsidered impossible because of locally advanced le-sions in 3 patients. Written informed consent was ob-tained from all patients.

This clinical trial was approved by the Ethics Com-mittee of Aichi Cancer Center Hospital.

MethodsTreatment schedule. The treatment schedule is

shown in Fig. 1. In patients who were not eligible forsystemic chemotherapy, including elderly patients(�75 yrs) and those with a poor PS score, arterialinjection chemotherapy was simultaneously performedduring radiation therapy. In patients in whom systemicchemotherapy was possible, alternating therapy involv-ing systemic chemotherapy and radiation therapy wasperformed. Arterial injection therapy was initiated afterthe end of the second course of systemic chemotherapy.

Arterial injection therapy. As previously reported,6-8

the anterior ear on the affected side was incised underlocal anesthesia to expose the superficial temporal ar-tery. During fluoroscopy, a thin catheter was selectivelyinserted into the lingual artery. When the lesion in-volved the contralateral side beyond the median line,another catheter was inserted on the contralateral sidefor bilateral arterial injection.

When the tumor involved the tongue, oral floor, andlower gingiva, a catheter was inserted into the externalcarotid artery. Before April 1999, a catheter with the

Table I. Patient characteristics

CharacteristicNo.

(n � 40)

Age, yMedian 68Range 25-87

Performance status (ECOG)0 71 242 83 1

GenderMale 26Female 14

Stage (1997 UICC)III 29T2N1M0: 6 T3N0M0: 18 T3N1M0: 5IVT3N2bM0: 3 T3N2cM0: 1 T4N0M0: 2 T4N1M0: 2

T4N2bM0: 2 T4N2cM0: 111

HistologySquamous cell carcinoma 40

ECOG, Eastern Cooperative Oncology Group; UICC, InternationalUnion Against Cancer.

type J end was hung in the orifice of the lingual artery

(Fig. 2). However, the catheter end dropped out of thelingual artery in some patients. Therefore, after May1999, a guide-wire was inserted into the periphery ofthe lingual artery, and a type J catheter was removed.Subsequently, a catheter with a tapered end was in-serted along the guide-wire to a deep area 3 to 4 cmdistant from the orifice of the lingual artery (Fig. 3).

Administration of the agent. Continuous arterial in-jection of CBDCA was performed using a portableelectrical pump for 4 to 6 weeks. Using Calvert’sformula,12 the total dose of CBDCA was established as6- to 8-fold the area under the plasma concentration-time curve (AUC) in accordance with kidney functionand general condition. In patients who received sys-temic chemotherapy, the total dose of CBDCA wasAUC 6.

We confirmed whether the extent of arterial injectioncovered the entire tumor by a blue dye, angiography,and magnetic resonance imaging (MRI) from Septem-ber 2000, in which an extremely low dose of contrastmedium for MRI was slowly infused via a catheter forarterial injection (Fig. 4).

Systemic chemotherapy. As a rule, arterial injectiontherapy was combined with systemic chemotherapy inpatients younger than 75 in whom systemic chemother-apy was possible, and the general condition and vis-ceral organ functions were maintained. The regimen ofsystemic chemotherapy consisted of continuous intra-

( a ) Systemic chemotherapy ( - )

( b ) Systemic chemotherapy ( + )

Ext. RT (Brachy)

CBDCA continuous infusion (AUC 6 - 8)

Ext. RTExt. RTCT CT (Brachy)

CBDCA continuous infusion (AUC 6)

Fig. 1. Scheme of the therapy. Two protocols of the combi-nation therapy of continuous intra-arterial (IA) infusion che-motherapy (CBDCA) and radiation therapy. A, In patientswho were not eligible for systemic chemotherapy, IA therapyis performed concurrently with radiation therapy. B, In pa-tients in whom systemic chemotherapy is possible, alternatingtherapy involving systemic chemotherapy and radiation ther-apy is performed. IA therapy is initiated after the end of thesecond course of systemic chemotherapy.

venous injection of 5-fluorouracil (5-FU) at 700 mg/m2

OOOOE716 Fuwa et al. June 2008

for 5 days (from Day 1 until Day 5) and intravenousdrip of nedaplatin (NDP) at 120 mg/m2 over 6 hours onDay 6. This regimen was performed twice at 3- to

Fig. 2. Digital subtraction angiography (DSA) of conven-tional selective intra-arterial infusion via superficial temporalartery (STA). The tip of the vinyl hook-shaped catheter(NECK, 4 Fr in outer diameter, Medikit Corp., Tokyo, Japan)was inserted into the left lingual artery. The contrast mediumwas seen to be flowing only in the lingual artery.

Fig. 3. DSA of new selective intra-arterial infusion via STA.The tip of the polyurethane straight catheter (ANTHRON P-Ucatheter; tapering type, 5 Fr in outer diameter, Toray MedicalCorp., Tokyo, Japan) was inserted into the left lingual artery.

4-week intervals.

Radiation therapy. Radiotherapy was performedwith 6 MV Linac X-ray. Irradiation was performed 5times a week at a radiation dose of 1.8 to 2 Gy. As arule, left-right, 2-opposed portals irradiation was per-formed until the total dose reached 36 to 40 Gy. Then,the irradiation field was reduced, and oblique 2-op-posed portals or conformation radiation therapy wasperformed until the total dose reached a target dose of66 to 70 Gy in accordance with individual patients. Inpatients in whom brachytherapy was possible, externalirradiation at a radiation dose of approximately 40 Gyor less was combined with brachytherapy using a Csneedle or Au grain.

PATIENT ASSESSMENTSConcerning toxicity, we investigated changes in the

leukocyte count, neutrophil count, platelet count, he-moglobin level, liver function, kidney function, oralmucosa, and vomiting in accordance with World HealthOrganization (WHO0 criteria.13 During treatment, thecomplete cell count was measured at least twice aweek, and blood biochemistry was performed once aweek. To evaluate the antitumor effects of tongue can-cer, visual examination, palpation, and MRI were per-formed within 1 month after the end of treatment. The

Fig. 4. Flow check by coronal view MRI. The contrast me-dium (2 mL Gd-DTPA with 20 mL saline) was infused intothe left lingual artery for 10 minutes. The extent of arterialinjection from left lingual artery could be confirmed by flowcheck of MRI.

treatment response of the cervical lymph nodes was

OOOOEVolume 105, Number 6 Fuwa et al. 717

evaluated based on the MRI or CT findings and thepalpation findings in accordance with the WHO crite-ria.

The subjects consulted the outpatient clinic at4-week intervals for 1 year after the end of treatment, at8-week intervals in the second and third years of fol-low-up, and at 3-month intervals after 3 years of fol-low-up. Follow-up MRI was performed at 4-monthintervals for 2 years after the end of treatment, and at6-month intervals thereafter. Chest radiography wasperformed at 6-month intervals, and liver CT and bonescintigraphy were performed every year until 3 yearsafter the end of treatment.

We calculated the local control rate, overall survival(OS) rate and, progression-free survival (PFS) rate bythe Kaplan-Meier method.14

Survival (local control) was calculated (as of October1, 2006, or the date of the last medical examination)using the start of treatment as the starting point. Incalculating PFS, the day on which an increase in thetumor size was confirmed, the day on which a newlesion was confirmed, and the day of death related toanother disease despite tumor control were regarded asevents. In calculating OS, deaths related to variouscauses were regarded as events.

RESULTSThe scheduled treatment was completed in 92.5% of

the patients (37/40: general physical deterioration in 2patients, refusal of therapy in 1 patient). In the 40patients, follow-up was performed, with a median fol-low-up of 27 months (3 to 159 months).

A catheter was inserted through the lingual artery in23 patients, through the external carotid artery in 11patients, through the faciolingual trunk in 2 patients,and through the bilateral lingual arteries in 3 patients.During the course, the route was changed from thelingual artery to the external carotid artery in 1 patient.The total dose of CBDCA in all patients ranged from150 to 1,300 mg, with a median of 570 mg. The totaldose of CBDCA in the scheduled treatment patientsranged from 300 to 1,300 mg, with a median of 590 mg.

The radiation dose of external beam in all patientsranged from 28.0 to 73.8 Gy, with a median of 46.8 Gy.The radiation dose of external beam in the scheduledtreatment patients without brachytherapy ranged from50.0 to 73.8 Gy, with a median of 63.0 Gy. Brachy-therapy was performed in 23 patients; interstitial irra-diation with a Cs needle was performed in 8 patients;and interstitial irradiation with Au grain was performedin 15 patients. Median dose of brachytherapy was 50Gy. Systemic chemotherapy was combined in 19 pa-

tients.

Treatment resultsComplete response (CR) was achieved in 29 patients,

partial response (PR) in 10 patients, and minor response(MR) in 1 patient. Relapse was detected in 17 patients:primary (tongue) sites, 9 patients; cervical lymph node,7 patients; primary site and cervical lymph node, 1patient. Of the patients with relapse, surgery was per-formed in 7 patients, intra-arterial chemoradiation in 4patients, radiation therapy in 1 patient, chemoradiationtherapy in 1 patient, and chemotherapy in 1 patient,respectively. Nineteen patients died; 16 patients died ofprimary diseases, and 3 patients died of other diseases.

The 5-year local control rate was 65% (Fig. 5). The5-year OS rate was 39.5%, and the 5-year PFS rate was32.5% (Fig. 6).

Acute toxicityAcute toxicity is summarized in Table II. Grade 3 or

higher toxic changes included granulocytopenia in 20patients, thrombopenia in 14 patients, anemia in 5 pa-tients, and mucositis in 2 patients. Grade 2 nephropathywas observed in only 1 patient. There were no transientor persistent central nervous system complications.

Chronic toxicityWe studied chronic toxicity in 26 patients who sur-

vived more than 12 months after the treatment. Al-though these 26 patients did not develop problems ofphonation and deglutition function and were able to eatnormally, continuous glossalgia was recognized in 1 ofthe patients. Sometimes use of an analgesic was nec-essary for this patient.

DISCUSSIONAs described earlier, in the 1990s, arterial injection

0

. 2

. 4

. 6

. 8

1

0 10 20 30 40 50 60

Loca

l con

trol

rat

e

months

Fig. 5. Actuarial local control curve in 40 patients withlocally advanced tongue cancer by Kaplan-Meier method.

therapy for head and neck cancer was reevaluated as a

OOOOE718 Fuwa et al. June 2008

new treatment option based on the following back-ground: the establishment of a procedure for selectiveinsertion of a catheter into the target artery,2-7 and theestablishment of arterial injection of CDDP with aCDDP-neutralizing agent, STS, in which the tumorlevel of CDDP is elevated without increasing adversereactions.2-5

In this study, we reviewed the treatment results in 40patients with stage III/IV tongue cancer who underwentchemoradiation therapy involving continuous arterialinjection of CBDCA. The 5-year local control, OS, andPFS rates were 62%, 31%, and 30%, respectively.Considering that surgery was impossible due to ad-vanced stage and old age in about 50% of the patients,these results were similar to the results of surgery.

Continuous arterial injection therapy with CBDCA

Table II. Acute toxicity

Toxicities (WHO criteria)

With systemic chem(n � 19)

0-2 3

HematologicWhite blood cell 11 4Granulocyte 11 5Platelet 11 5Hemoglobin 15 3

NonhematologicHepatic dysfunction 19 0Renal dysfunction 19 0Vomiting 19 0Mucocitis 18 1Neuropathy 19 0Fever 19 0

0

. 2

. 4

. 6

. 8

1

0 10 20 30 40 50 60

months

Sur

viva

l rat

e

Fig. 6. Actuarial survival curves in 40 patients with locallyadvanced tongue cancer by Kaplan-Meier method. Thick line,overall survival curve; thin line, progression-free survivalcurve.

WHO, World Health Organization.

less markedly exacerbated mucositis in elderly patients.In most patients, oral ingestion was possible duringtreatment. The most adverse effects were bone marrowtoxicity; however, white blood cells or platelets de-creased rather slowly, so it was easy to control bonemarrow toxicity.

When the tumor is localized in the tongue, the lin-gual artery nourishes the tumor in most patients. Afteradministration of anticancer agents, essentially all ofthe dose will reach the tumor. Therefore, arterial injec-tion therapy may be most appropriate for tongue canceramong various types of head and neck cancer. Severalstudies have reported on arterial injection therapy fortongue cancer15-19; however, the number of patientswas small, and no study has described the long-termresults of treatment. Our study is the first report on thelong-term results of intra-arterial chemotherapy in alarge number of tongue cancer patients.

The results of radiotherapy for locally advancedtongue cancer alone were poor.20-23 Currently, surgeryis the standard treatment. After a resection of half of thetongue, phonatory and deglutition functions are rela-tively maintained; however, subtotal resection or moreextended surgery results in severe functional disordersaffecting the patient’s quality of life. If this nonsurgicaltreatment achieves a local control rate similar to thatachieved by surgery, this treatment will be a veryimportant option for patients with locally advancedtongue cancer.

To further improve the LCR, we modified the pro-cedure described by Robbins et al2,3: CDDP at 20 to 30mg/m2 was infused over 5 hours once a week or twicea week via a catheter inserted into the lingual artery,and simultaneously neutralized by intravenous drip ofSTS. The dose of CDDP was approximately one sixthof that described by Robbins et al.2,3 and Kerber et al4;

py Without systemic chemotherapy(n � 21)

4 0-2 3 4

4 10 9 23 9 9 33 15 3 31 19 1 1

0 21 0 00 21 0 00 21 0 00 20 1 00 21 0 00 19 2 0

othera

OOOOEVolume 105, Number 6 Fuwa et al. 719

however, the duration of administration was 60 timeslonger. It has been reported that the antitumor effects ofCDDP are correlated with the concentration and dura-tion of administration24-26; low-dose CDDP may ex-hibit potent antitumor effects. Although the follow-upperiod is short, potent local effects look promising.

We will evaluate this method by accumulation ofdata from more patients, and it is expected to be auseful therapeutic option for patients with locally ad-vanced tongue cancer.

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Reprint requests:

Nobukazu Fuwa, MDDepartment of Radiation OncologyAichi Cancer Center HospitalKanokoden, Chikusaku, Nagoya464-8681, Japan

nfuwa@aichi-cc.jp