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(Radiology. 1999;213:173-179.)
© RSNA, 1999

Vascular and Interventional Radiology

T1 and T2 Lip Cancer: A Superselective Method of Facial Arterial Infusion Therapy-Preliminary Experience1

Kazushi Kishi, MD, PhD, Masahiro Matsunaka, MD, PhD, Morio Sato, MD, PhD, Tetsuo Sonomura, MD, PhD, Mikihisa Sakurane, MD and Koji Uede, MD

1 From the Departments of Radiology (K.K., M. Sato, T.S.) and Dermatology (M.M., M. Sakurane, K.U.), Wakayama Medical College, Wakayama City, Japan. Received April 6, 1998; revision requested May 22; final revision received December 3; accepted March 17, 1999. Supported in part by a grant in aid for cancer therapy from the Japanese Ministry of Welfare, 1994, 1995, 1996, and 1997, as part of the Study of Clinical Evaluation of Interventional Radiology in Cancer Management. Address reprint requests to K.K., Department of Radiology, Wakayama Medical College, Kimiidera 811-1, Wakayama City, 641-0012 Japan (e-mail: SachiKishi@aol.com).


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To formulate and evaluate a facial arterial infusion chemotherapy for squamous cell lip carcinoma.

MATERIALS AND METHODS: The study included six patients (age range, 46–84 years) with squamous cell carcinoma of the lower lip. There were two T1 tumors, three T2 tumors, and one T1-compatible postoperative recurrent tumor. A 4-F, double-lumen balloon catheter was inserted into the external carotid artery through the superficial temporal artery and placed for selective infusion into the tumor-feeding facial artery. Patients received a combination of mitomycin C (4.4 mg/m2 per body surface area) on day 1 and 3.2 mg/m2 of peplomycin sulfate on days 1–7 (22.4 mg/m2 per week), or, when peplomycin sulfate was contraindicated, 16 mg/m2 of cisplatin only on days 1–5 (80 mg/m2 per week). Two to three cycles of chemotherapy were given until tumor disappearance was histologically confirmed.

RESULTS: Complete tumor disappearance was achieved in all cases. One patient had a self-limiting asthma attack during peplomycin sulfate treatment, and another had transient partial hair loss. No disfigurement, recurrence, or late complications were observed at a mean follow-up of 5.0 years (range, 2.3–11.2 years).

CONCLUSION: The described facial arterial infusion chemotherapy appears to be a safe and curative treatment for T1 and T2 squamous cell lip carcinomas.

Index terms: Angiography, 262.124 • Catheters and catheterization, 905.1266 • Chemotherapeutic infusion, 262.1266 • Face, neoplasms, 262.373


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Early (T1 and T2) stage squamous cell carcinoma of the lip has been treated mainly with surgery and alternatively with radiation therapy (1,2). High curative rates and relatively good cosmetic results are obtained with both modalities in the early stages of disease (3). Chemotherapy, on the other hand, has not had a major role in the treatment of lip cancer (4). In head and neck cancer, most systemic or regional chemotherapy is used for induction (in combination with radiation) or for palliative purposes in the case of advanced cancer (5–8). However, the results of some clinical studies indicate that squamous cell carcinoma of the head and neck may be quite sensitive to chemotherapy (9,10). Attempts to increase the therapeutic effect of systemic or regional chemotherapy in the head and neck region include increasing the dose intensity (systemic effects or systemic pharmacokinetics with a dose regimen such as milligrams per square meter per week) (11) and improving superselective catheterization techniques in arterial infusion chemotherapy (5,7).

Superselective regional arterial infusion could prove to be advantageous in the treatment of early squamous cell carcinoma of the lip, because this tumor is fed exclusively by the inferior labial artery (12). By taking advantage of advancements in balloon catheters (13–17) and the commercial availability of an inexpensive portable infuser that is widely used in pain control, we were able to formulate a technique to provide daily infusion chemotherapy to the facial artery (18). This technique involves selective facial arterial infusion—either with a combination of mitomycin C and peplomycin sulfate, which is an analogue of bleomycin that has less pulmonary toxicity, or with cisplatin only—by means of a temporarily implanted balloon catheter to control arterial flow. In this study, six patients with squamous cell carcinoma of the lip were treated with facial arterial infusion therapy and followed up to determine the efficacy of treatment. The purpose of this study was to develop and assess the usefulness of a superselective method of facial arterial infusion chemotherapy for squamous cell lip carcinoma.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Inclusion Criteria
Patients who had squamous cell carcinoma of the lower lip in clinical stage I or II or a local recurrent tumor compatible with these stages in tumor size were included in this study when surgery or radiation therapy (19,20) was contraindicated or when the patient refused these treatments. Patients were excluded if they met any of the following criteria: age older than 85 years, presence of distant metastasis, poor kidney or hepatic function, bone marrow suppression, severe cerebrovascular or cardiovascular disease, prior systemic chemotherapy, or prior radiation therapy (for a previous tumor in the same area) because this could decrease the blood supply to the tumor (21).

Patients
From 1987 to 1997, six patients (four men, two women; mean age [± SD], 54.4 years ± 30.0; age range, 46–84 years) with squamous cell carcinoma of the lower lip were enrolled. The clinical stages of the primary cancer according to the TNM system were stage I (T1N0M0) in two patients and stage II (T2N0M0) in three patients; the sixth patient had a postoperative recurrence of tumor that was compatible with stage I cancer (T1N0M0) (Table). No accompanying premalignant lesions were found. The mean size of the tumors (± SD) was 17.7 mm ± 10.9 in diameter (range, 5–35 mm) and 20.5 mm ± 10.7 in width (range, 10–35 mm). One patient had pulmonary fibrosis that caused hypoxia, and another had diabetes and a high leukocyte count due to local tumor infection. All patients had a Karnofsky performance status of at least 80% (ie, ability to perform normal activities with effort, with some signs or symptoms of disease). Two patients had been treated with 5-fluorouracil ointment (22) for 2–3 weeks at local hospitals; however, despite this treatment, their tumors had grown. The reasons for enrollment in this protocol were advanced age (older than 75 years) in three, postoperative tumor recurrence in one, underlying diabetes in one, refusal to undergo surgery in one, and refusal to be treated with radiation therapy in all. All patients signed an informed consent form before the study began.


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  		Summary of Cases
 
Chest radiography, computed tomography (CT) of the lip and neck, bone scintigraphy, and gallium scintigraphy were performed for tumor staging and detection of metastasis. Before and after each treatment cycle, patients underwent complete clinical and laboratory examinations, which included the following: complete blood cell count; platelet count; differential blood cell count; prothrombin time; partial thromboplastin time; urinalysis; analysis of creatinine, electrolyte, and magnesium levels; 24-hour urinalysis for creatinine clearance; and audiography.

Protocol Design
Each treatment cycle lasted 2 weeks. The drug dosage consisted of a combination of mitomycin C (4.4 mg/m2 per body surface area) on day 1 and 3.2 mg/m2 of peplomycin sulfate on days 1–7 (22.4 mg/m2 per week), or, when peplomycin sulfate was contraindicated, 16 mg/m2 of cisplatin only on days 1–5 (80 mg/m2 per week). The dose of cisplatin was decreased to 26.7 mg/m2 or 53.3 mg/m2, one-third or two-thirds of 80 mg/m2, respectively, when the patient was infirm or older than 80 years. All drugs were superselectively infused into the facial artery through a balloon catheter that was temporarily implanted into the external carotid artery under flow control by using the hemostatic balloon, which was inflated during drug infusion. The cycles were repeated until disappearance of the tumor was histologically confirmed; the maximum number of cycles was three. The balloon catheter was then removed. This protocol was performed with institutional approval.

Preparatory Angiographic Evaluations
Superselective transfemoral diagnostic angiography was performed by using the standard Seldinger technique. Immediately after insertion of the vascular sheath, 2,000 U of heparin was infused intravenously to prevent thromboembolic complications related to the catheter procedure, and 1,000 U of heparin was intravenously infused every 60 minutes during the procedure. The contrast medium (300 mg of iodine/mL of iopamidol) used for angiography also contained heparin (10 U/mL) (6,7). A 5-F heparin-coated catheter (SAA5000A; Toray, Tokyo, Japan) was used for external or internal carotid angiography. A 3-F microcatheter (Transend-Ex46-805; Medi-tech/Boston Scientific, Watertown, Mass) and an 0.018-inch hydrophilically coated guide wire (Venture 18-510; Medi-tech/Boston Scientific) were used for superselective facial angiography.

A digital subtraction angiographic study (23) was performed to identify the vessels feeding the tumor and the vascular anatomy on both sides of the common carotid artery, external carotid artery, facial artery, and inferior labial artery (first ramus of the facial branch of the facial artery [12]). Conformation of the faciolingual trunk (12) and any unusual communication between the facial artery and the branch of the internal carotid artery were checked to avoid misdirecting the drug (24). Absence of an aberrant tumor feeder through an anastomosis with the opposite side of the inferior labial artery or with the mental branch of the inferior alveolar artery also was confirmed.

The balloon catheter was positioned to effectively infuse drugs into the facial artery while sparing the distal branches of the external carotid artery, such as the occipital and internal maxillary arteries. The tip of the balloon catheter was placed as close as possible to the inlet of the facial artery but kept 0.5–1.5 cm away from the inlet, depending on the patient's individual vascular anatomy, to avoid stimulation of the facial arterial wall by the catheter tip or balloon inflation.

The color dye infusion test was performed to determine (a) which artery was feeding the tumor, (b) whether the balloon catheter was properly positioned, and (c) an appropriate infusion rate. A solution of 1% indigo carmine (Daiichi Seiyaku, Tokyo, Japan) diluted with saline to 0.5% was infused into the facial arteries through a catheter, and the distribution of the dye was observed. Unexpected or unfavorable distribution of the dye was thoroughly searched for in the entire head and neck region.

Temporary Implantation of Balloon Catheter
After the angiographic evaluations, a superficial temporal artery was selected by making a preauricular skin incision with the patient under local anesthesia with 0.1% lidocaine, and the artery was punctured with a 24-gauge, elastic cannula and needle. Through the elastic cannula, a soft-tipped hydrophilic guide wire (Transend; Medi-tech/Boston Scientific) was inserted and advanced retrogradely into the external carotid artery. Over this guide wire, a flexible 4-F, double-lumen balloon catheter (Barman AI-07134; Arrow International, Reading, Pa) was introduced and advanced so that it was just peripheral to the bifurcation of the facial artery. The balloon was inflated with about 0.2 mL of saline and adjusted to the inner diameter of the artery for complete occlusion (Fig 1).



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  		Figure 1. Facial arterial infusion with a balloon catheter. A double-lumen balloon catheter is inserted from the superficial temporal artery into the external carotid artery. When the balloon is inflated to occlude the external carotid artery, the infused drugs are selectively delivered into the facial artery.

 
With this occlusion technique, the blood flow in the facial artery was kept completely patent because there was no direct interference into the facial artery itself nor into its proximal vessels. Similar or relevant balloon catheter techniques in cancer therapy have been reported elsewhere (13–17,25–28). Weakened pulsation at the temporal artery and occipital artery was confirmed, whereas the pulsation of the facial artery was not reduced. The contrast medium that was test infused through the balloon catheter was fluoroscopically confirmed to be flowing exclusively into the facial artery. The color dye was infused to confirm sufficient distribution over the tumor, and this infusion rate was recorded. The balloon was then deflated, and the catheter was fixed by using sutures. If areas supplied by the other arteries such as the lingual, occipital, or superficial temporal artery were stained blue, then the catheter was properly relocated before it was fixed in place. When both the right and left facial arteries fed the tumor, bilateral catheter insertion was performed. The infusion branch of the double-lumen catheter was connected to a portable continuous infusion pump (Infuser 2C1080; Baxter, New York, NY) filled with a solution of heparin and saline, which was infused at an hourly rate of 41.6 U heparin per 0.5 mL of saline to prevent catheter obstruction and thrombus formation.

Drug Infusion
Facial arteries, occipital arteries, and carotid arteries were palpated daily to confirm their patency. The balloon catheter was checked for obstruction or leakage by applying negative pressure to both the balloon site and the infusion site connectors. The infusion route was then flushed with a 5-mL solution of heparin and saline. The balloon was inflated to control the blood flow, and the dye infusion test was repeated. After a sufficient distribution of the dye was observed at the appropriate infusion rate, the drug solution was infused at the same rate under flow control after the occlusion balloon was inflated. Mitomycin C, which was prepared as a 0.5 mg/mL saline solution, and peplomycin sulfate, which was prepared as a 0.25 mg/mL saline solution, were infused for 10 minutes. Cisplatin, which was prepared as a 0.25 mg/mL saline solution, was infused for 40 minutes, which included two balloon-deflating intermissions that lasted 5 minutes each. The flow rate was not altered when the dose of cisplatin was changed. For hydration and diuretic therapy, patients received a drip infusion of 500 mL of saline before and of 300 mL of mannitol after the infusion of cisplatin (29,30).

Daily Observation
Patients were observed for nausea, vomiting, diarrhea, stomatitis, and fever and for signs or symptoms of circulatory or respiratory dysfunction, infection, cutaneous toxicity, allergy, ototoxicity, and central or peripheral nervous system disturbance.

Weekly Examination
The patients who were receiving peplomycin sulfate were examined with chest radiography during treatment to check for pneumonia, fibrosis, or pleural effusions. In all patients, the following laboratory examinations were performed: leukocyte count, platelet count, hematocrit level, blood urea nitrogen level, and urinalysis for Eastern Cooperative Oncology Group (ECOG) toxicity criteria (31).

Tumor Evaluation
The size and appearance of the tumors were checked every day during treatment. Biopsy was performed when the tumor was no longer visible or palpable and again 1 month after the first biopsy. After the treatment was finished, as determined by negative biopsy results, the physicians in charge maintained contact with the patients to follow their progress. Toxicity was evaluated according to ECOG criteria (31).


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The results of digital subtraction angiography proved that no arterial communication or arterial variants could have influenced the procedure in any of the patients. One patient had a distinct hypervascular tumor stain at angiography (Fig 2).



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  		Figure 2a. (a) External carotid arterial angiogram (lateral view) obtained in a 68-year-old woman (case 5) shows a moderately hypervascular tumor stain (short arrow) at the end of the inferior labial artery (curved arrow). The external carotid artery (long arrow) also is seen. (b) Superselective facial angiogram (lateral view) obtained in the same patient by using the implanted balloon catheter during balloon inflation shows no distal branches of the external carotid artery (long arrow). The balloon head (arrowhead) and facial artery (short arrow) also are seen.

 


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  		Figure 2b. (a) External carotid arterial angiogram (lateral view) obtained in a 68-year-old woman (case 5) shows a moderately hypervascular tumor stain (short arrow) at the end of the inferior labial artery (curved arrow). The external carotid artery (long arrow) also is seen. (b) Superselective facial angiogram (lateral view) obtained in the same patient by using the implanted balloon catheter during balloon inflation shows no distal branches of the external carotid artery (long arrow). The balloon head (arrowhead) and facial artery (short arrow) also are seen.

 
Color dye infusion tests resulted in definitive tumor staining and discrimination of the area fed by the artery in all patients (Fig 3a) (6,7). All of the untreated tumors were proved to be fed exclusively by a single facial artery. In the one patient who had a postoperative recurrence of tumor, the bilateral facial arteries supplied the tumor from both sides to a central sagittal suture line on the tumor. No unfavorable distribution of the dye was found. All catheter implantation procedures were successful. The infusion rates ranged from 0.1–0.3 mL/sec.



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  		Figure 3a. Photographs of treatment progression in the patient in Figure 2 (case 5). (a) Before treatment, tumors (arrows) with central ulceration are observed in the center of the lower lip. (b) Two months after treatment, there is no disfigurement (ie, shortening, contraction, or scar formation) of the lip.

 


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  		Figure 3b. Photographs of treatment progression in the patient in Figure 2 (case 5). (a) Before treatment, tumors (arrows) with central ulceration are observed in the center of the lower lip. (b) Two months after treatment, there is no disfigurement (ie, shortening, contraction, or scar formation) of the lip.

 
Infusion Therapy
Fourteen cycles (range, two to three cycles per patient) of facial arterial infusion were performed in six patients. The first cycle of the combination of peplomycin sulfate and mitomycin C was stopped in one patient because of an asthma attack, which did not recur either during or after the second cycle of cisplatin only. In the fifth patient, the second course was interrupted on day 5 because of a kink in a portion of the catheter close to the infusion pump, and the third course was finished in 3 days because of tumor disappearance.

Response
All tumors showed an apparent decrease in size from that in the 1st week of treatment. In every case, the tumor completely disappeared. The results of both the first and second posttreatment biopsy were negative. All patients recovered without disfigurement within 2 months after the end of infusion therapy (Fig 3b).

Survival
At the time this article was written, no recurrence of carcinoma had been observed at a mean follow-up of 59.5 months (range, 27–133 months). Six years after treatment, one patient died of a sudden cardiovascular attack at the age of 90 years, without either recurrence or complications of tumor.

Complications
During the treatment, four patients complained of slight pain near the pharynx or subparotid region; this pain spontaneously disappeared. Nausea occurred in three patients during cisplatin treatment. Fever below 38°C was observed in three patients. One patient had transient hair loss in the ipsilateral occiput because of incomplete balloon occlusion of the artery during the first cycle; the hair grew back after 2 months. One patient had an asthma attack with hypoxia on the 4th day of peplomycin sulfate infusion but recovered soon after the drug was stopped. No other acute or late complications nor any other toxicity of ECOG grades 1–4 were observed.


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Facial arterial infusion therapy resulted in the complete disappearance of early squamous cell carcinoma of the lip, with recurrence-free, long-term survival in all six patients. Although only six patients were enrolled in this study because of our restrictive enrollment criteria, we believe the results are definitive.

To clarify our rationale for this therapy, we first reviewed other strategies for early-stage lip cancer. Early (T1 or T2) lip cancer has been treated mainly by using surgery or, alternatively, by using radiation therapy (1–3). High curative rates—about 95% or greater—and good cosmetic results in the majority of cases have been achieved with both modalities (1–3, 32,33). Surgery offers rapid treatment and complete extirpation of tumor. However, surgical treatment results in a greater loss of nonmalignant tissue than do radiation therapy and chemotherapy. This is because subclinical peripheral tumor extension at least 1 cm beyond the clinical margin is reportedly found in 70% of tumors (34).

A complete V-shaped, W-shaped, or rectangular resection causes variable distortion of the lip, which may require reconstruction (2). Radiation therapy is used mainly as an alternative treatment in elderly or infirm patients or in patients who are at substantial risk for anesthesia-related complications or recurrent or advanced cancer. Radiation therapy may cause late damage such as dental caries, osteoradionecrosis, or atrophy of the lip musculature (3). In short, neither surgery nor radiation therapy is entirely free from problems.

Chemotherapy has not had a definitive role in the treatment of lip cancer (4). Squamous cell carcinomas of the skin of the head and neck (including the lip) are generally slow growing, similar to basal cell carcinoma, but this does not mean that they are resistant to chemotherapy (1). The results of several clinical studies (9,35,36) of systemic chemotherapy for head and neck skin cancers indicate that these tumors may be quite sensitive to chemotherapy. In one such study (9), it was reported that in three patients who received three to five cycles of systemic infusion of doxorubicin (50 mg/m2) and cisplatin (50 mg/m2) (or carboplatin [200 mg/m2]), squamous cell carcinoma of the facial skin completely disappeared. In another study (35), it was reported that the basal cell carcinoma in two patients responded completely after four to seven cycles of systemic infusion of 60–80 mg/m2 of cisplatin (35). In yet another study (36), the advanced squamous cell carcinoma of the skin in four of 11 patients responded completely after four cycles of combination chemotherapy with 100 mg/m2 of cisplatin on day 1, a continuous infusion of 650 mg/m2 of 5-fluorouracil on days 1–5, and 15–16 mg/m2 of bleomycin on days 1–6. Unfortunately, systemic toxicity of ECOG grades 3–4 and pulmonary fibrosis were frequently observed in these patients (9,36).

Intraarterial infusion chemotherapy was administered to benefit from the pharmacokinetic advantage R provided in the first pass of the drug through the tumor bed, which is expressed as follows: R = 1 + CLTB/Q, where CLTB is the total clearance of the drug from the body plasma and Q is the local plasma flow (11,37).

To date, we know of only two available reports on the use of the described modality to treat lip cancer (10,18). Stephens et al (10) reported an almost total regression or disappearance of the tumor in four of 11 patients with advanced carcinoma of the lower lip after one to six cycles (median, three; average, 2.9) of external carotid arterial infusion of bleomycin (15 mg) on days 1 and 5, vincristine (0.6 g/m2) on day 2, actinomycin D (1.5 mg) on day 3, and methotrexate (30 mg/m2) on day 5. The substantial side effects observed in nine of these 11 patients included a painful ulcerated mouth in four, temporary hemiparesis due to catheter dislodging into the common carotid artery in one, temporary hair loss in five, sour mouth in four, febrile reaction to bleomycin in one, and leukocytopenia or thrombocytopenia in two patients. The other report is that from our previous study of the same technique in two patients (18).

There have been many clinical trials of intraarterial infusion therapy through the external carotid artery for head and neck tumors. The results of trials in the 1970s demonstrated the marginally superior effectiveness of intraarterial infusion, which was tempered by a high prevalence of catheter-related complications (38). Besides these complications, several substantial limitations were known: (a) A rheologic laminar flow phenomenon can cause unbalanced drug distribution, as is often the case with continuous arterial infusion without turbulence. (b) Many head and neck cancers have multiple or parasitic feeder arteries (5–7). (c) Placement of the catheter is difficult in some cases. (d) The pharmacokinetic advantage is not easy to estimate. When rapid washout from the tumor bed results in a steeper decline in the concentration curve than that with systemic plasma clearance, poor enhancement of the area under the curve occurs (29). A trial of continuous slow infusion therapy with cisplatin and floxuridine through the external carotid artery by means of an implantable port or a pump resulted in a complete response in only two of 27 patients with advanced cancers of the head and neck (39).

To improve the effectiveness of intraarterial infusion therapy for head and neck cancer, high-dose chemotherapy (11,40) and superselective techniques (5,7) have been used. The results of an investigation of high-dose cisplatin therapy showed response rates to be dependent on dose intensity; the overall response rates were 46% (five of 11 patients), 82% (nine of 11 patients), and 100% (nine of nine patients) for dose intensities of below 74, 75–149, and 150–200 mg/m2 per week, respectively (40).

Response rates similar to those in the high-dose trial (40) were achieved in investigations in which the following superselective infusion therapies with a relatively small dose intensity were used: 30–40 mg/m2 of cisplatin once a week (complete response in 38% [five of 13 patients], partial response in 54% [seven of 13 patients]) (6) and either 50 mg/m2 of cisplatin or 300 mg/m2 of carboplatin once a week (complete response in 50% [13 of 26 patients], partial response in 46% [12 of 26 patients]) (7). In the superselective infusion therapies, infusion of all the feeding branches from the external carotid artery was performed by using a microcatheter that was coaxially inserted each time by means of the Seldinger technique through the femoral artery with fluoroscopically guided placement of the catheter tip. No catheter-related complications were experienced in a total of 99 treatments.

When the target vessel is small, such as the facial artery is, the equation of the pharmacokinetic advantage can be incorporated with the Poiseuille law (ie, in laminar flow, the volume of a homogeneous fluid that passes through a capillary tube per unit of time is directly proportional to the pressure difference between its ends and to the fourth power of its internal radius, and is inversely proportional to its length and to the viscosity of the fluid); however, other corrective considerations must be factored in. Then, the tumor plasma flow rate is estimated to be proportional to the fourth power of the artery's internal radius. When the diameters of the internal carotid artery, external carotid artery, and facial artery are 5.0, 3.0, and 1.6 mm, respectively, as in case five (Fig 2), the pharmacokinetic advantage of cisplatin is calculated to be 130, although the pharmacokinetic advantage of external carotid arterial infusion is calculated to be only 11.3. This calculation was made as follows: When the blood flow in the internal carotid artery is 300 mL/min (41), the blood flow in the facial artery can be calculated as 3.1 mL/min according to the Poiseuille law. Then the pharmacokinetic advantage is 1 + CLTB/Q, where CLTB = 400 mL/min, Qexternal carotid artery = 38.9 mL/min, and Qfacial artery = 3.1 mL/min.

Forastiere et al (39) calculated the pharmacokinetic advantage of the external carotid arterial infusion of cisplatin to be 5 on the basis of a rough estimation of the external carotid flow as one-third of the internal carotid artery flow. This greater pharmacokinetic advantage value means that superselective infusion into a small artery can strongly enhance the effect of intraarterial chemotherapy without increasing the total dose intensity in the whole body. In addition, it suggests a practical solution to overcoming active drug resistance by increasing the local concentration (42,43). The drugs in the active resistance group, such as cisplatin, show convex survival curves, with a "shoulder" in the low-dose range followed by a steep linear course when the survival is plotted against the drug dose on a log scale (42,44).

In contrast to many other malignant tumors that are frequently supplied by multiple or parasitic arteries (5,7), early cancer of the lower lip is fed by one inferior labial artery. We confirmed that this was the case in five of the six patients in our study; the sixth patient had a postoperative recurrent tumor that was fed by bilateral facial arteries. This anatomic factor allowed the effective use of a temporary in-dwelling balloon catheter to perform repeated superselective infusions.

There are two basic techniques of balloon-occluded intraarterial infusion therapy. One technique is to occlude a feeding artery and infuse drugs into it to provide a higher drug concentration. This technique is used in the liver and pelvic organs, which are fed by two or more blood supplies (15–17,25–28,43,45,46). The other technique is to occlude and preserve the nonfeeding arteries and thus avoid direct insertion of the catheter into the feeding artery (13,14,18,39); we used this technique in the present study. We preferred to use the latter method because it has the advantage of enabling one to avoid the vascular spasms that frequently result from direct stimulation of the arterial wall by the inserted catheter (45–47). Persistent arterial spasms would make this route unsuitable for constant intraarterial infusion therapy (5). Another pharmacologic advantage of using the latter method is preservation of the blood flow and oxygen supply into the target organ, because cellular sensitivity to many anticancer drugs, including mitomycin C and bleomycin, is reported to be substantially altered under hypoxic conditions (43,45,46).

Intraarterial infusion therapy for head and neck tumors has been reported to be associated with a high risk of serious complications such as cerebral stroke and neurotoxic events (5,38,39). Intraarterial infusion for a tumor invading the intracranial space may lead to misdirection of the drug through artery-to-artery communications. All anatomic sites supplied by the facial artery are at risk for drug-induced damage during the described therapy, and any communication between the angular artery and the central retinal artery should be carefully checked. The inferior labial artery itself should not communicate with the intracranial system. In short, facial arterial infusion should be considered to be one of the safer treatments that is available for intraarterial infusion for head and neck cancer.

One of our concerns was to avoid normal tissue necrosis. On the basis of the calculation previously discussed, drug toxicity increases with decreased local plasma flow (11,37). The results of an experimental study (44) showed dose-dependent normal tissue necrosis to occur with decreased tissue plasma flow. However, in the clinical environment, it is almost impossible to determine the individual local plasma flow in different patients, and the dose-response relationship may differ in each case. This issue might be worth further investigation. Because the number of cases studied here was small, an optimal dose must be elucidated after additional experience.

In conclusion, the described method of facial arterial infusion therapy for squamous cell carcinoma of the lip is a curative treatment that is at least as effective as surgery or radiation therapy, without the disfigurement. Although this study involved a small number of patients, the complete response rate and long-term recurrence-free survival warrant the continued exploration of this treatment modality.


   Footnotes
 
Abbreviation: ECOG = Eastern Cooperative Oncology Group

Author contributions: Guarantor of integrity of entire study, K.K.; study concepts and design, K.K.; definition of intellectual content, M. Sato; literature research, K.K., M.M.; clinical studies, M. Sakurane, T.S., K.U.; data acquisition, K.K., M.M.; data analysis, K.K.; manuscript preparation and editing, K.K.; manuscript review, M. Sato.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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