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Original Research |
1 Both authors: Department of Radiology, Niigata Cancer Center Hospital, 2-15-3, Kawagishi-cho, Niigata 951-8566, Japan.
Received May 1, 2005;
accepted after revision September 21, 2005.
Address correspondence to H. Seki
(hseki{at}niigata-cc.jp).
Abstract
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SUBJECTS AND METHODS. Fifty patients with unresectable malignant liver tumors underwent radiologic implantation of catheter-port systems using the long tapered catheter placement method. A 2.7-French distal shaft of the catheter was inserted distally in the hepatic artery with its side hole located proximally, and a 5-French proximal shaft was placed in the aorta; the catheter tip was not fixed. Technical success, complications including catheter stability and hepatic artery patency, and tumor response were assessed and compared with the following two historical controls: 35 patients with a 5-French catheter inserted simply in the hepatic artery (conventional method), and 131 patients with a 5-French catheter, the tip of which was fixed in the gastroduodenal artery (the fixed-catheter-tip method).
RESULTS. The technical success rate using the long tapered catheter placement method was 92% (46/50 patients), whereas the feasibility of the fixed-catheter-tip method was confined to 79% of historical controls (131/166 patients). Among patients in whom the gastroduodenal artery was present, a decreased frequency of gastroduodenal artery embolization was seen using the long tapered catheter placement method (39%; 17/44 patients) compared with the conventional method (p = 0.0112) and the fixed-catheter-tip method (p < 0.0001). Cumulative stability rates of the catheter (6 months, 94.9%; 1 year, 94.9%; 2 years, 86.2%) and cumulative patency rates of the hepatic artery (6 months, 89.9%; 1 year, 89.9%; 2 years, 83.5%) were significantly higher using the long tapered catheter placement method than using the conventional method (p = 0.0208 and p = 0.0066, respectively) but were similar to those using the fixed-catheter-tip method. The time of hepatic tumor progression was significantly longer using the long tapered catheter placement method than using the conventional method (p = 0.0299) but was comparable to the time using the fixed-catheter-tip method.
CONCLUSION. The long tapered catheter placement method should find wider application in hepatic arterial infusion chemotherapy because it is useful in preventing catheter dislodgment and hepatic artery occlusion.
Keywords: catheters • infusion chemotherapy • hepatic arteries • interventional radiology • implantable devices • liver
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For unresectable liver metastases, hepatic arterial infusion chemotherapy has been widely used as a regional therapy, and a significant response rate is achieved despite poor control of extrahepatic progression [5-8]. On the other hand, for patients with liver metastases from colorectal cancer, current clinical trials involving systemic chemotherapy using irinotecan and oxaliplatin, combined with 5-fluorouracil-based regimens, have shown improved survival [9, 10]. However, response rates and times to hepatic progression are superior in patients receiving hepatic arterial infusion chemotherapy compared with those receiving systemic treatment [5-10]. In an attempt to prevent extrahepatic progression, combinations of hepatic arterial infusion with systemic chemotherapy are currently being investigated [11, 12]. In addition, recent studies have reported the effectiveness of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma [13, 14]. Therefore, hepatic arterial infusion chemotherapy using catheter-port systems is an important therapy for unresectable liver malignancies.
Radiologic implantation of catheter-port systems is an easier and safer procedure than surgical implantation, and it does not require administration of general anesthesia [15-17]. However, frequent catheter dislodgment and hepatic artery occlusion were noted as major limitations of radiologic implantation using conventional catheter placement, in which an end-hole catheter is simply inserted into the common or proper hepatic artery [17-21]. To resolve these problems, catheter placement using the fixed-catheter-tip method has been developed, in which the tip of a catheter is fixed in the gastroduodenal artery using coils or liquid glue [17-20].
However, several limitations still remain: This method is inadequate when the gastroduodenal artery is absent or too short; many arterial branches, including the gastroduodenal artery, must be embolized to avoid extrahepatic perfusion and to stabilize the catheter; and removing the catheter in cases of catheter dysfunction is troublesome because hepatic artery occlusion may result from migration of embolic agents. Also, thrombosis of critical organs, such as cerebral infarction, may occur because of thrombi clinging to the tip of the catheter [20].
We have developed a radiologic implantation method for catheter-port systems using a long tapered side-hole catheter in which a small-caliber (2.7-French), 20-cm-long distal shaft with a side hole is inserted distally into the hepatic artery, and a larger (5-French) proximal shaft is placed in the aorta (the long tapered catheter placement method). The purpose of our study was to prospectively evaluate the feasibility and safety of the long tapered catheter placement method, and to assess stability of the catheter and the patency of the hepatic artery during hepatic arterial infusion chemotherapy, compared with the conventional method and the fixed-catheter-tip method.
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Small extrahepatic disease confirmed by radiologic examinations or intraoperative findings was not considered an absolute contraindication if the liver was the predominant site of disease. Three patients had hepatocellular carcinoma, and 47 had liver metastases from colorectal cancer (n = 23), gastric cancer (n = 19), pancreatic cancer (n = 2), bile duct cancer (n = 1), esophageal cancer (n = 1), and lung cancer (n = 1). Ten of these patients had recurrent liver tumors after resection of the liver: wedge resection in three, lateral or right posterior segmentectomy in two, left hepatic lobectomy in two, and both wedge resection and lateral segmentectomy in three patients.
For comparison, 166 patients with catheterport systems using a 5-French indwelling catheter were studied retrospectively. These patients had been treated from approximately 5 years to 1 month before this study. These historical controls were divided into the following two groups: 35 patients received the catheter-port system using the conventional method, in which a catheter was simply inserted into the proper or common hepatic artery, and 131 patients were treated using the fixed-catheter-tip method, in which the catheter tip was fixed into the gastroduodenal artery using coils, with the side hole placed in the common hepatic artery.
Technical Procedure
All procedures were performed in the radiology suite using an angiography
unit. Before catheter placement, angiography was performed via a transfemoral
route for arterial road mapping and arterial redistribution for all patients
[20,
21,
23]. When we encountered an
aberrant hepatic artery, we decided to implant an indwelling catheter into the
larger hepatic artery, and the smaller hepatic artery was embolized using
coils (FPC35 Pt-Max and VortX, Boston Scientific; Tornado, Cook) to convert
the multiple hepatic arteries into a single arterial blood supply. In
addition, extrahepatic arterial branches arising from the hepatic artery were
occluded, if necessary, using coils to avoid extrahepatic perfusion of
chemotherapeutic drugs.
Catheter placement was performed several days after angiography was performed. For premedication, 15 mg of pentazocine hydrochloride and 25 mg of hydroxyzine pamoate were given by an intramuscular injection. The procedure was done under local infiltration anesthesia using 1% procaine hydrochloride. In 47 of 50 patients, the left axillary artery was chosen as the access route using the following technique: A skin incision was made under the left clavicle approximately 4 cm long; the axillary artery was surgically exposed and its arterial branch, mainly the thoracoacromial artery, was cut down; a 5-French, 30-cm-long introducer sheath (Supersheath, Medikit) was inserted via this branch into the descending aorta.
For the remaining three patients who had undergone prior angiography revealing that the celiac artery arose from the abdominal aorta at an acute angle, the inferior epigastric artery was used as the access route using the following procedure: A 0.032-inch guidewire (Radifocus, Terumo) was inserted into the inferior epigastric artery with a contralateral transfemoral approach; the skin of the lower abdominal wall was incised and the inferior epigastric artery was exposed; the guidewire was pulled through a small incision in the inferior epigastric artery, and a 5-French, 10-cm-long introducer sheath (Supersheath) was advanced into the external iliac artery over this guidewire [17]. A long tapered-type catheter was used as an indwelling catheter (Anthron P-U Catheter, Toray). This was composed of a 2.7-French distal shaft 20 cm long and a 5-French proximal shaft that was 70 cm long. The catheter was made of polyurethane and its surface was coated with heparin. This catheter has been approved by the Ministry of Health, Labor, and Welfare of Japan for clinical application as an implantable medical device.
In the long tapered catheter placement method used in this study, a slit-type side hole approximately 2 or 3 mm long and approximately 0.5 mm wide was made manually using small scissors in the 2.7-French distal shaft of the catheter. The 2.7-French distal shaft with the side hole was then placed at the abdominal aorta near the origin of the celiac artery trunk or the superior mesenteric artery and extending to a peripheral branch of the hepatic artery with no fixation of the catheter tip (Figs. 1A, 1B, 1C, 2A, and 2B), and the 5-French proximal shaft was placed between the aorta and the access artery.
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Hepatic arterial infusion chemotherapy was started after an initial check of the catheter-port system using digital subtraction angiography, CT, and hepatic arterial perfusion scintigraphy. The following chemotherapeutic drugs were used: 5-fluorouracil (1,000 mg/m2 weekly in a 5-hour infusion) was administered to patients with liver metastases from colorectal cancer; 5-fluorouracil (330 mg/m2 weekly in a 3-hour infusion), mitomycin C (2.7 mg/m2 biweekly in a bolus infusion), and epirubicin (30 mg/m2 every 4 weeks in a bolus infusion) for patients with liver metastases from gastric, pancreatic, and bile duct cancer; and 5-fluorouracil (1,000 mg/m2 weekly in a 5-hour infusion) and cisplatin (10 mg weekly in a bolus infusion) for patients with hepatocellular carcinoma and liver metastases from esophageal and lung cancer.
Among the 166 patients who were historical controls, the arterial access technique was performed in the same manner, and the 5-French catheter was made of polyurethane with a surface coating of heparin similar to that used in our study. In addition, the regimens of hepatic arterial infusion chemotherapy were similar to those used in this study.
Follow-Up
Patients were followed until the end of the hepatic arterial infusion
chemotherapy. Abdominal radiography, digital subtraction angiography via the
implanted catheter, CT arteriography using the catheter-port system, or
hepatic arterial perfusion scintigraphy was performed within 10 days after
implantation of the catheter-port system and every 2-3 months thereafter to
assess the position of the catheter, patency of the hepatic artery, and
perfusion pattern in the liver. Digital subtraction angiography was performed
during injection of the contrast medium through the catheter-port system. CT
arteriography using the catheter-port system was performed through the entire
liver, in which the contrast medium of 100 mg I/mL of iopamidol (Iopamiron,
Schering) was injected via the implanted port at a rate of 0.7 mL/s, and data
acquisition began 20 seconds after initiation of injection
[17,
24]. Hepatic artery perfusion
scintigraphy was performed using 370 MBq of technetium-99m macroaggregated
albumin in 10 mL of saline, which was infused for 1 hour through the implanted
port at a rate of 10 mL/h. In general, hepatic arterial perfusion scintigraphy
was performed during the initial perfusion study, and CT arteriography was
performed at the initial and follow-up evaluations. These imaging procedures
were also performed when patients complained of any symptoms related to
hepatic artery infusion with chemotherapeutic drugs. In addition, a whole-body
CT examination was performed before treatment and every 3 months thereafter to
evaluate treatment responses.
Evaluation of Technical Outcomes
We evaluated the technical success using the long tapered catheter
placement method. In addition, we recorded what kind of artery was occluded
when coils were used to avoid extrahepatic perfusion of infused drugs because
of the arterial anatomy.
Evaluation of catheter stability, hepatic artery patency, other complications, catheter dysfunction, and perfusion pattern—During the follow-up period, stability of the catheter and patency of the hepatic artery were assessed. They were measured from the date of catheter placement until the date of catheter dislodgment or hepatic artery occlusion, or until the end of the hepatic arterial infusion chemotherapy. In addition, other complications such as catheter dysfunction and perfusion abnormality were evaluated.
Evaluation of tumor responses—The objective tumor response was assessed using an abdominal CT examination. Responsive cases were defined as those with a 50% or more decrease in the sum of the products of the perpendicular diameters of the lesions. Nonresponsive cases were described as a 50% or less decrease, or any increase, in the sum of the areas of the indicator lesions.
Statistical Analysis
Comparisons of patient characteristics for the three groups treated with
the long tapered catheter placement method, the conventional method, and the
fixed-catheter-tip method were performed using the chi-square test and
Fisher's exact probability test. In addition, completion of embolization of
the gastroduodenal artery and the objective tumor response were compared among
the three groups using these tests. The cumulative stability rate of the
catheter, the patency rate of the hepatic artery, and the time to hepatic
progression were calculated using the Kaplan-Meier method, and the resultant
curves were compared using the log-rank test. Statistical significance was
established with a p value of less than 0.05.
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2 mm in diameter) to introduce the catheter
distally. For these patients, we judged that the hepatic artery might be
occluded if the catheter was implanted into it. Therefore, the
fixed-catheter-tip method was used instead. For the one remaining patient,
arterial stenosis was found at the junction between the common and the proper
hepatic arteries, probably as a result of postoperative changes after a prior
pancreatoduodenectomy. Therefore, a modified fixed-catheter-tip method was
selected in which the side hole of the catheter was placed in the celiac
artery trunk and the catheter tip was fixed into the splenic artery using
coils. The hepatic artery into which the long tapered side-hole catheter was inserted, and the position of the catheter, are presented in Table 1. The long tapered side-hole catheter was inserted into the hepatic artery arising from the celiac artery in 38 patients (Figs. 1A, 1B, and 1C) and into the aberrant hepatic artery arising from the superior mesenteric artery in eight patients (Figs. 2A and 2B). Among these patients, the gastroduodenal artery was absent because of pervious surgery in two patients.
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The catheter could be implanted using the fixed catheter-tip method in 131 (79%) of 166 historical patients. The conventional method was used for the remaining 35 patients, in whom the gastroduodenal artery was absent or was too short to fix the catheter tip because of previous surgery.
Embolization of Extrahepatic Arterial Branches
The rate of completion of embolization of the gastroduodenal artery to
avoid extrahepatic perfusion is listed in
Table 2. Among patients in whom
the gastroduodenal artery was present, the gastroduodenal artery was embolized
using coils in 17 (39%) of 44 patients because of the following causes: For 14
patients the side hole of the catheter had to be placed in the common hepatic
artery or the proper hepatic artery immediately near the origin of the
gastroduodenal artery because of a short proper hepatic artery; for the
remaining three patients, the gastroduodenal artery was occluded when the
origin of the proper hepatic artery was embolized using coils to convert the
hepatic artery blood flow into the replaced right hepatic artery arising from
the superior mesenteric artery.
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For the remaining 27 patients, however, embolization of the gastroduodenal artery was not required for the following reasons: The side hole of the catheter could be placed in the proper hepatic artery at a distance from the origin of the gastroduodenal artery in 23 patients (Figs. 1A, 1B, and 1C), and the catheter was inserted in the replaced right or proper hepatic artery arising from the superior mesenteric artery in four patients (Figs. 2A and 2B). On the other hand, using the conventional method, the gastroduodenal artery was embolized using coils in 17 (71%) of 24 patients because the catheter had to be placed in the common hepatic artery as a result of the difficulty of stable catheter placement in the proper hepatic artery. Using the fixed-catheter-tip method, the gastroduodenal artery was occluded using coils for all patients (100%). The frequency of embolization of the gastroduodenal artery was significantly lower using the long tapered catheter placement method than using the conventional method (p = 0.0112) or the fixed-catheter-tip method (p < 0.0001).
The right gastric artery, which originated from the proper or left hepatic artery, if present, was occluded using coils to prevent gastric toxicity resulting from any catheter placement method (Figs. 1A, 1B, and 1C). A posterosuperior pancreaticoduodenal artery arising from the proper hepatic artery and an accessory left gastric artery arising from the left or proper hepatic artery were found on angiography in 4 and 3 patients, respectively, who were treated with the long tapered catheter placement method; in 3 and 1 patient, respectively, treated with the conventional method; and in 6 and 13 patients, respectively, treated with the fixed-catheter-tip method. All of these were occluded using coils (Figs. 1A, 1B, and 1C). In addition, the dorsal pancreatic artery arising from the common hepatic artery was embolized using coils in 3 patients who were treated with the conventional method, and in 12 patients treated with the fixed-catheter-tip method.
Stability of the Catheter and Patency of the Hepatic Artery
After implantation of catheter-port systems using the long tapered catheter
placement method, 46 patients were followed up for a mean period of 283 days
(range, 38-928 days). Among the historical controls, the mean follow-up period
was 255 days (range, 17-1,260 days) for 35 patients treated using the
conventional method and 259 days (range, 16-1,162 days) for 131 patients
treated using the fixed-catheter-tip method. Patient characteristics are shown
in Table 3. The variables
listed show no significant differences between patients among the three arms
of the catheter placement method study.
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Catheter dislodgment data are listed in Table 4. Dislocation of the catheter was found using follow-up digital subtraction angiography through the catheter-port system in three (6.5%) of 46 patients treated with the long tapered catheter placement method. No correlation was seen between the access route and catheter dislodgment. The patients had no clinical symptoms related to dislocation of the catheter. They did not require repositioning of the catheter because the gastroduodenal artery had been occluded using coils at the implantation of the catheter-port system in two patients, and the gastroduodenal artery had hepatopetal blood flow in the third patient.
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Among historical controls treated using the conventional method, catheter dislodgment was seen in eight patients. Of these patients, the catheter was repositioned in four patients and systemic chemotherapy was substituted, resulting in progressive disease in these four patients. In the other control group treated with the fixed-catheter-tip method, catheter dislocation was seen in four patients. In these patients, the catheter was not removed and hepatic arterial infusion chemotherapy was continued thereafter. For two of these patients, however, dosage reduction of infused drugs was required. The cumulative stability rates of the catheters used in the long tapered catheter placement method were 94.9%, 94.9%, and 86.2% at 6 months, 1 year, and 2 years, respectively. These were significantly higher than those for the conventional method (p = 0.0208) but were similar to those using the fixed-catheter-tip method; in the latter case, no statistically significant difference was seen (p = 0.3836) (Fig. 3).
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Among the historical controls, hepatic artery occlusion was seen in 11 patients treated with the conventional method and in 16 patients treated with the fixed-catheter-tip method. All received systemic chemotherapy thereafter. Among these patients, progressive disease was subsequently seen in 23 patients, whereas the substituted treatment was effective in four patients. For patients treated with the long tapered catheter placement method, cumulative patency rates of the hepatic artery at 6 months, 1 year, and 2 years were 89.9%, 89.9%, and 83.5%, respectively. Statistically significant better patency of the hepatic artery occurred in patients treated with the long tapered catheter placement method than in those treated with the conventional method (p = 0.0066), whereas no statistically significant difference was seen compared with results for the fixed-catheter-tip method (p = 0.4739) (Fig. 4).
Other Complications, Catheter Dysfunction, and Perfusion Pattern
Complications, catheter dysfunctions, and perfusion abnormalities are
summarized in Table 5. For the
long tapered catheter placement method, except for hepatic artery occlusion
and catheter dislodgment, major complications did not occur. Occlusion of the
catheter was not seen and the side hole of the catheter was patent during the
follow-up period. In two patients, a collateral blood supply to the liver
developed. Collateral vessels were confirmed using angiography via a
transfemoral approach, and they were embolized to correct intrahepatic drug
distribution.
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Initial perfusion studies using the catheterport system showed a sufficient distribution through the entire liver in all 46 patients treated with the long tapered catheter placement method. Angiography was performed just after catheter implantation and showed that the contrast medium flowed from both the side hole and the end hole of the implanted catheter. Follow-up digital subtraction angiography through the implanted catheter showed that the outflow from the side hole of the catheter became predominant compared with that from its end hole. CT arteriography using the catheter-port system, however, showed that hypoperfusion in the liver where the catheter was inserted distally was not seen in any patients.
Tumor Response and Time to Hepatic Progression
Tumor response and the time to hepatic progression are presented in
Table 6. No statistically
significant difference was seen in the objective tumor response rate among the
three arms of the catheter placement method study. However, the time to
hepatic progression was significantly longer for patients treated with the
long tapered catheter placement method than for those treated with the
conventional method (p = 0.0299) but was comparable to the time
associated with the fixed-catheter-tip method (p = 0.6293).
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The long tapered catheter placement method used in this study does not require fixation of the catheter tip. Also, if necessary, the catheter can be removed easily and safely. In our study, the long tapered catheter placement method could be used in 92% of patients, regardless of the presence or absence of the gastroduodenal artery, whereas the fixed-catheter-tip method was feasible in only 79% of historical controls. In addition, compared with the conventional method and the fixed-catheter-tip method, the long tapered catheter placement method had a decreased frequency of embolizing the gastroduodenal artery because the side hole of the catheter could be placed stably in the proper hepatic artery in many cases.
The stability rate of the catheter and the patency of the hepatic artery were significantly higher in patients treated with the long tapered catheter placement method than in those treated with the conventional method, and were comparable to rates for patients treated with the fixed-catheter-tip method. In the long tapered catheter placement method, catheter insertion distally in the hepatic artery contributed to a reduction in mobility of the catheter, resulting in a decreased incidence of catheter dislocation and a reduced mechanical stimulation of the arterial wall. In addition, using this method, the distal shaft of the catheter placed in the hepatic artery had a small caliber (2.7 French) and was made of a soft material (polyurethane) coated with heparin. These characteristics made it less likely to generate hepatic artery thrombosis. Catheter dislodgment and hepatic artery occlusion may decrease the effectiveness of hepatic arterial infusion chemotherapy because of temporary or permanent interruption of the intraarterial infusion of drugs.
In our study, the time to hepatic progression was significantly longer for patients treated with the long tapered catheter placement method than for those treated with the conventional method, and was comparable to the time required for those treated with the fixed-catheter-tip method. Although the control groups in this study were historical, these results indicate that the long tapered catheter placement method is comparable to the fixed-catheter-tip method with respect to preventing catheter dislodgment and hepatic artery occlusion.
In our study, the fixed-catheter-tip method was used instead of the long tapered catheter placement method for a few patients in whom the caliber of the proper hepatic artery was too small to insert the catheter distally. Therefore, the fixed-catheter-tip method will still be applicable as an alternative catheter placement method in these special circumstances.
In conclusion, the long tapered catheter placement method should find wide application because it is an easy interventional procedure and it will help prevent catheter dislodgment and hepatic artery occlusion during hepatic arterial infusion chemotherapy. We believe that this method can be used for radiologic implantation of catheter-port systems instead of the current standard, the fixed-catheter-tip method, although alternative methods still must be used in some cases.
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= long tapered
catheter placement method, censored cases; 
= conventional method,
censored cases; X = fixed-catheter-tip method, censored cases. Stability rates
in patients treated with long tapered catheter placement method were
significantly higher than those for patients treated with conventional method
(p = 0.0208 using log-rank test) but were similar to rates for those
treated with fixed-catheter-tip method.