Interventional Radiology Original Research

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1 Interventional Radiology Original Research Seki et al. Side-Hole Catheter Placement for HAI Chemotherapy Interventional Radiology Original Research Hiroshi Seki 1 Toshirou Ozaki Makoto Shiina Seki H, Ozaki T, Shiina M Keywords: catheter-port system, chemotherapy, colorectal cancer, hepatic artery, liver metastases, side-hole catheter DOI: /AJR Received February 11, 2007; accepted after revision July 10, Supported by the Japanese Society of Implantable Port Assisted Regional Treatment (JSIPART), but this assistance did not influence the content of this study. 1 All authors: Department of Radiology, Niigata Cancer Center Hospital, , Kawagishi-cho, Chuo-ku, Niigata , Japan. Address correspondence to H. Seki (hseki@niigata-cc.jp). AJR 2008; 190: X/08/ American Roentgen Ray Society Side-Hole Catheter Placement for Hepatic Arterial Infusion Chemotherapy in Patients with Liver Metastases from Colorectal Cancer: Long-Term Treatment and Survival Benefit OBJECTIVE. The objective of this study was to evaluate retrospectively correlations between catheter placement methods and treatment outcomes of patients treated with hepatic arterial infusion chemotherapy for unresectable liver metastases from colorectal cancer. MATERIALS AND METHODS. This study involved 135 patients with liver metastases from colorectal cancer who underwent intrahepatic chemotherapy using catheter-port systems. Complications, treatment discontinuation, hepatic progression, and survival of patients treated with each method were evaluated retrospectively using the Kaplan-Meier method. Conventional 5-French end-hole catheter placement (n = 10) was compared with three side-hole catheter placement methods: 5-French side-hole catheter placement with a fixed catheter tip (original fixed catheter tip method, n = 77); long tapered side-hole catheter placement using a fixed catheter tip method (modified fixed catheter tip method, n = 24); and long tapered side-hole catheter inserted distally in the hepatic artery (long tapered catheter placement method, n = 24). RESULTS. The following treatment outcomes were significantly better for patients treated using the original or modified fixed catheter tip or long tapered catheter placement method than for those treated using the conventional method, respectively: hepatic arterial patency (1 year: 76.3%, 95.0%, and 94.4% vs 38.9%; p = , , and ), catheter stability (1 year: 96.7%, 95.5%, and 95.2% vs 42.9%; p < , p = , and p = ), time to treatment discontinuation (medians: 11.7, 14.4, and 12.4 vs 3.2 months; p < , , and ), time to hepatic progression (medians: 14.7, 15.7, and 15.8 vs 5.5 months; p = , , and ), and overall survival (medians: 21.1, 22.5, and 23.1 vs 13.1 months; p = , , and ). CONCLUSION. Compared with the conventional method, side-hole catheter placement methods allowed long-term intrahepatic chemotherapy and resulted in improved survival. L iver metastases are a major cause of mortality in patients with colorectal cancer. Although surgical resection can offer long-term survival for patients with isolated liver metastases, most patients are not suitable candidates for resection [1, 2]. Recent clinical trials involving systemic chemotherapy using irinotecan and oxaliplatin added to 5-fluorouracil (5-FU) and leucovorin (LV) have shown improved survival in patients with advanced colorectal cancer [3, 4]. On the other hand, hepatic arterial infusion (HAI) chemotherapy is also used as an effective treatment for patients with liver metastases from colorectal cancer. However, of the randomized trials that have compared HAI chemotherapy with systemic chemotherapy, few found significant differences in survival, even though the response rates for HAI chemotherapy were superior to those for systemic therapy [5 13]. These previous studies have been criticized because patients who experienced disease progression after receiving systemic chemotherapy were allowed to cross over to HAI chemotherapy and also because catheterrelated problems, which occurred frequently in patients allotted to the HAI chemotherapy treatment arm, resulted in treatment failure and confounded assessments of survival impact. Recently, a randomized trial that did not allow treatment crossover showed significantly longer survival for patients who underwent HAI chemotherapy than for those who underwent systemic chemotherapy [14]. We decided to examine whether further improvement in survival could be attained using catheter-port systems implanted using procedures designed to avoid catheter-related complications. Radiologic implantation of catheter-port systems is regarded as an easier and safer procedure than surgical implantation [15 23]. A simple catheter placement method has been AJR:190, January

2 Seki et al. TABLE 1: Patient Characteristics in the Four Placement Method Groups Characteristics Conventional Method (n = 10) used widely for radiologic implantation, in which an end-hole catheter is inserted into the common or proper hepatic artery (i.e., the conventional method). However, frequent catheter dislodgment and hepatic arterial occlusion have been noted as major limitations of this method [15 18]. To overcome these drawbacks, several methods based on the use of side-hole catheters have been developed, such as the fixed catheter tip method, in which a catheter loop with a side hole is placed into the common hepatic artery with the catheter tip fixed in the gastroduodenal artery using coils [19 22]. Another method is the long tapered catheter placement method, in which a long tapered side-hole catheter is inserted distally into the hepatic artery with the side hole located proximally [23]. Several investigators have reported that these new methods were useful in preventing catheter dislodgment and hepatic arterial occlusion [17 23]. However, to our knowledge, the impact of these side-hole catheter placement methods on survival has not yet been assessed. The purpose of our study was to evaluate retrospectively the correlation between Side-Hole Catheter Placement Method Original Fixed (n = 77) Modified Fixed (n = 24) Long Tapered Catheter Placement (n = 24) Age (y) > Sex 0.72 Male Female Performance status Liver involvement % > 60% Extrahepatic lesions 0.16 Yes No Prior chemotherapy 0.50 Yes No a Comparison of patient characteristics between the groups treated by either the conventional method or the side-hole catheter placement methods. The p values were calculated using the Fisher s exact probability test. catheter placement methods and outcome of HAI chemotherapy treatment in patients with unresectable liver metastases from colorectal cancer, with a focus on the impact of the sidehole catheter placement methods on survival. Materials and Methods Patients At our institution between May 1995 and October 2005, we implanted catheter-port systems for HAI chemotherapy in 135 patients (95 men and 40 women; age range, years; mean age, 62.0 years) with unresectable liver metastases from colorectal cancer. Treatment outcomes and survival assessed in this study were evaluated retrospectively. The study was approved by the ethics committee at our institution. Informed consent concerning catheter placement and HAI chemotherapy was obtained from each patient before commencement of the procedures. The patients were enrolled sequentially in the study. For inclusion in the study, patients were required to have unresectable liver metastases from colorectal cancer, a serum bilirubin level of less than 3.0 mg/dl, and a performance status of 2 or less according to the Eastern Cooperative Oncology p a Group classification [24]. Small extrahepatic disease confirmed by radiologic examination or intraoperative findings was not considered an absolute contraindication for catheter placement if the liver was the predominant site of disease. Prior treatment for metastatic disease was permitted if the last dose had been administered at least 2 weeks before the date of catheter placement. The patients characteristics grouped according to catheter placement method are summarized in Table 1. The coexistence of extrahepatic lesions was observed more frequently in the groups treated with the side-hole catheter placement methods than those in the conventional method group. However, no statistically significant differences for any of the listed variables were observed between the patients grouped according to the conventional method and the patients treated with side-hole catheter placement methods. Catheter Placement Procedures All procedures were performed in the radiology suite with an angiography unit by two operators who had 9 and 2 years of experience in interventional radiology at the initiation of this study. Before catheter placement, angiography was performed in all patients via the transfemoral route for arterial road mapping and arterial redistribution [25 27]. When an aberrant hepatic artery was encountered, hepatic arterial blood flow was redistributed using coils (FPC35 Pt-Max and VortX, Boston Scientific; and Tornado, Cook) to convert multiple hepatic arteries into a single arterial blood supply. If necessary, extrahepatic arterial branches arising from the hepatic artery and parasitic arteries with hepatopetal blood flow were also occluded using coils or a mixture of N-butyl cyanoacrylate (Histoacryl, Braun) and iodized oil (Lipiodol, Guerbet). Catheter placement was performed several days after angiography while the patient was under local anesthesia. In 122 of the 135 patients, the left axillary artery was chosen as the access route because of the absence of a wide range of motion in the region through which the catheter passed [15, 19]. In these patients, a branch of the axillary artery mainly, the thoracoacromial artery was surgically exposed under the left clavicle, and a 5-French, 30-cm-long introducer sheath (Supersheath, Medikit) was inserted via this branch into the descending aorta. In the remaining 13 patients, in whom prior angiograms revealed the celiac artery rising from the abdominal aorta at an acute angle, the inferior epigastric artery was used as the access route by performing the following procedure [19]: A inch guidewire (Radifocus, Terumo) was inserted into the inferior epigastric artery using a contralateral transfemoral approach. The skin of the lower abdominal wall 112 AJR:190, January 2008

3 Side-Hole Catheter Placement for HAI Chemotherapy was then 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 the guidewire. An indwelling catheter made of polyurethane with a heparincoated surface (Anthron P-U catheter, Toray) was A D Fig. 1 Four types of catheter placement methods. A, Schematic diagram shows conventional method: 5-French end-hole catheter is simply inserted in common hepatic artery. Gastroduodenal artery (arrows) and right gastric artery (arrowhead) are then embolized using coils. B, 75-year-old woman with liver metastases from sigmoid colon cancer. Arteriogram via catheter-port system shows catheter placement using conventional method. Gastroduodenal artery (arrows) and right gastric artery (arrowhead) are embolized using coils. C, Schematic diagram shows original fixed catheter tip method: 5-French side-hole catheter is implanted in hepatic artery, with side hole of catheter placed in common hepatic artery and distal catheter shaft fixed within gastroduodenal artery by coils (straight arrows). Inside lumen of tapered catheter tip is occluded using microcoil (curved arrow). Right gastric artery is embolized using coils (arrowhead). D, 49-year-old man with liver metastases from sigmoid colon cancer. Arteriogram via catheter-port system shows catheter placement using original fixed catheter tip method. Distal shaft of catheter is fixed in gastroduodenal artery using coils (thin black arrows), with side hole located in common hepatic artery. Inside lumen of catheter tip is occluded using microcoil (white arrow). Posterior superior pancreaticoduodenal artery (thick black arrow), accessory left gastric artery arising from left hepatic artery (large arrowhead), and right gastric artery (small arrowhead) are embolized by coils. E, Schematic diagram shows modified fixed catheter tip method. Long tapered side-hole catheter is implanted, in which 2.7-French, 20-cm-long distal loop of catheter is inserted in hepatic artery, with side hole placed in common hepatic artery, and tip and distal shaft of catheter fixed in gastroduodenal artery by coils (arrows). Even if coils do not reach around catheter tip, lumen of tip of 2.7-French catheter is coagulated and closed spontaneously. Right gastric artery is then embolized by coils (arrowhead). F, 72-year-old man with liver metastases from transverse colon cancer. Arteriogram via catheter-port system shows catheter placement using modified fixed catheter tip method. Tip and distal shaft of long tapered catheter are fixed in gastroduodenal artery by coils (arrows), with side hole placed in common hepatic artery. Right gastric artery (large arrowhead) and posterior superior pancreaticoduodenal artery (small arrowhead) are embolized by coils. (Fig. 1 continues on next page) then inserted through these access routes into the hepatic artery. Finally, the proximal end of the catheter was cut and connected to a port (Soph- A-Port, Sophysa). The port was implanted into the subcutaneous space at the left anterior chest wall or the lower abdominal wall in patients using an access route via the left axillary artery or the inferior epigastric artery, respectively. B E Between 1995 and 2000, a 5-French sidehole catheter was usually implanted, in which the side hole was placed in the common hepatic artery and the tip of the catheter was fixed in the gastroduodenal artery (the original fixed catheter tip method; Figs. 1C and 1D) using the following procedure. After a side-hole catheter was placed in the hepatic artery, a second catheter was introduced C F AJR:190, January

4 Seki et al. into the gastroduodenal artery via the transfemoral route. Coils were then inserted around the tip of the side-hole catheter through the second catheter, and the distal loop of the catheter was fixed in the gastroduodenal artery. Finally, the inside lumen of the tapered tip of the catheter was occluded with a microcoil (VortX or Tornado). The microcoil was inserted through a microcatheter (On the Road, Solution, or Prograte, Terumo) that was advanced coaxially inside the indwelling catheter beyond the side hole [19, 21, 22]. A 5-French end-hole catheter was simply placed in the proper or common hepatic artery (the conventional method; Figs. 1A and 1B) in the following cases: In three patients, the gastroduodenal artery was absent due to previous surgery; in three patients, the gastroduodenal artery arose from the hepatic artery at an acute angle; in two patients, the gastroduodenal artery had hepatopetal blood flow; and two patients disliked the procedure involving fixation of the catheter tip. Between 2001 and 2005, a long tapered sidehole catheter composed of a 2.7-French, 20-cmlong distal shaft and a 5-French, 70-cm-long proximal shaft was usually implanted using the following methods: Either a 2.7-French distal catheter loop with a side hole was placed in the same manner as the original fixed catheter tip method (the modified fixed catheter tip method; Figs. 1E and 1F) [20, 22], or a 2.7-French distal catheter shaft was inserted distally into the hepatic artery with no fixation of the catheter tip and a side hole located proximally (the long tapered catheter placement method; Figs. 1G and 1H) [23]. At first, the modified fixed catheter tip method was used mainly to replace the original fixed catheter tip method, with the aim of reducing mechanical stimulation of the hepatic arterial wall by the use of a distal catheter loop with a small caliber (2.7-French). The long tapered G catheter placement method was introduced later and became the preferred method because of a decrease in the frequency of embolization of the gastroduodenal artery. The improvement observed with the long tapered catheter placement method was due to stable placement of the side hole of the catheter in the proper hepatic artery at a distance from the origin of the gastroduodenal artery in many cases. In addition, in cases in which the fixed catheter tip method was unsuitable, the long tapered catheter placement method was selected instead of the conventional method. As a result, in our study, catheter-port systems were implanted using the conventional method in 10 patients, the original fixed catheter tip method in 77, the modified fixed catheter tip method in 24, and the long tapered catheter placement method in 24. Administration of Chemotherapy HAI chemotherapy was initiated 2 14 days after catheter placement. For HAI chemotherapy, 5-FU (1,000 mg/m 2 ) was administered weekly as 5-hour infusions [28], a regimen that has been used for a considerable time in Japan as the standard regimen of HAI chemotherapy for liver metastases from colorectal cancer. This chemotherapeutic regimen did not change during the course of this retrospective review. Nine of the 135 patients had serum bilirubin levels of greater than 2.0 mg/dl and complained of epigastric pain due to hepatomegaly. In these patients, 5-FU at 167 mg/m 2 was infused over 5 days every week for the first 3 6 weeks and then weekly thereafter as described earlier. Patients received HAI chemotherapy until one of the following conditions was observed: progressive liver disease, extrahepatic disease progression predominant over the hepatic lesions, catheter dysfunction and complications that prevented H Fig. 1 (continued) Four types of catheter placement methods. G, Schematic diagram shows long tapered catheter placement method. Long tapered side-hole catheter is introduced into hepatic artery; 2.7-French, 20-cmlong distal loop of catheter is inserted distally into peripheral hepatic artery, with side hole placed in proper hepatic artery. Right gastric artery is occluded using coils (arrowhead). It is not necessary to embolize gastroduodenal artery when side hole is in stable position in proper hepatic artery. H, 56-year-old-man with liver metastases from rectal cancer. Arteriogram via catheter-port system shows catheter implantation using long tapered catheter placement method. Long tapered catheter loop is inserted distally into hepatic artery, with side hole placed in proper hepatic artery. Right gastric artery is embolized by coils (arrow). In addition, right inferior phrenic artery (arrowheads), which has parasitic blood supply to liver, is occluded using mixture of N-butyl cyanoacrylate and iodized oil. further treatment, or excessive toxicity. In the event of a partial response, the original regimen was continued for an additional 3 6 months, with a 30% dose reduction or biweekly administration of the drug being implemented thereafter. In the event of a complete response, treatment was continued for another 3 months and was followed by a 50% reduction in HAI chemotherapy dosage administrated biweekly or monthly for at least 3 months thereafter. Surgical resection of metastases was authorized in the event of a good response to HAI chemotherapy. After withdrawal from HAI chemotherapy, further treatment was left to the discretion of the investigators. Evaluation of Catheter-Port System and Treatment In all cases, assessments of perfusion patterns in the liver, catheter position, and patency of the hepatic artery were performed using CT arteriography and digital subtraction angiography via the catheter-port system [19] 1 10 days after catheter implantation and then every 2 or 3 months thereafter. Imaging was also performed when patients complained of any symptoms relating to HAI of the chemotherapeutic drugs. As part of normal care, whole-body CT was performed in all patients before treatment and then every 3 months to evaluate response to treatment. Imaging was assessed in consensus by experienced radiologists (21, 9, and 2 years of experience in diagnostic radiology, interventional radiology, or both at the initiation of this study). These prospective analyses were collated as part of the collection of retrospective data. During the follow-up period, patency of the hepatic artery and stability of the catheter were assessed. These were measured from the time of catheter placement until the time of hepatic arterial occlusion, catheter dislodgment, or the end of HAI chemotherapy. Other complications, 114 AJR:190, January 2008

5 Side-Hole Catheter Placement for HAI Chemotherapy catheter dysfunction, and perfusion abnormalities were also evaluated. In addition, time to treatment discontinuation was calculated from the time of catheter placement to the conclusion of HAI chemotherapy treatment. World Health Organization (WHO) criteria [29] were used to assess tumor response. A complete response was defined as disappearance of all radiographically apparent tumors for at least 4 weeks on CT scans, a partial response required at least a 50% decrease in the sum of the products of the perpendicular diameters of the lesions for at least 4 weeks, stable disease was described as a 50% or less decrease or a 25% or less increase in the sum of areas of the measurable lesions, and progressive disease was defined as any increase in tumor size over stable disease or the appearance of any new lesions. Tumor measurements exceeding 50% of the previously observed reduction also constituted disease progression. Time to hepatic progression was calculated from the time of catheter placement until documented progression of liver disease. For patients who had isolated liver metastases before HAI chemotherapy, time to extrahepatic progression was measured from the time of catheter placement to documented progression outside the liver. Overall survival was calculated from the time of catheter placement to death or last contact. The following parameters were compared between groups treated with one of the side-hole catheter placement methods and those treated with the conventional method: patency rates of the hepatic artery and stability rates of the catheter, time to treatment discontinuation, tumor response rates, time to hepatic or extrahepatic progression, and overall survival. We evaluated the effectiveness of the side-hole catheter placement methods in preventing catheter-related complications, especially hepatic arterial occlusion and catheter dislodgment, and in achieving long-term treatment. We also assessed whether enhanced control of hepatic tumors resulting from long-term intrahepatic chemotherapy led to an improvement in survival. Statistical Analysis Comparisons of patient characteristics in the four groups treated with the conventional method, the original fixed catheter tip method, the modified fixed catheter tip method, or the long tapered catheter placement method were performed using the Fisher s exact test. Objective tumor responses were compared among the four groups using the chi-square test. Hepatic artery cumulative patency rate, cumulative stability rate of the catheter, time to treatment discontinuation, time to hepatic progression, time to extrahepatic progression, and overall survival were calculated using the Kaplan- Meier method and were compared using the logrank test. Statistical significance was established for p values less than Results Complications, Catheter Dysfunction, and Perfusion Abnormalities Catheter-port systems were implanted successfully and HAI chemotherapy treatment was initiated in all patients, with a mean follow-up period of 569 days (range, 50 2,873 days). The incidences of procedurerelated complications, catheter dysfunction, and perfusion abnormalities are summarized in Table 2. Procedure-related complications Procedure-related complications occurred during or immediately after catheter implantation in four patients with the original fixed catheter tip method. However, these problems were promptly resolved. In one patient, the microcoil used to fix the tip of the catheter in the gastroduodenal artery during the catheter implantation procedure migrated to a peripheral branch of the hepatic artery. However, the hepatic arterial branch was not occluded and intrahepatic perfusion was maintained. In another patient, a local hematoma around the port occurred immediately after implantation of the catheter, but it resolved spontaneously with prolonged manual compression. Thrombosis of the axillary artery was seen immediately after catheter implantation via the axillary artery in two patients. Local thrombolysis using the transfemoral approach was performed in these patients, with satisfactory recanalization being achieved. Hepatic arterial patency and catheter stability During the follow-up period, hepatic arterial occlusion observed in 25 (18.5%) of the 135 patients led to discontinuation of HAI chemotherapy treatment (conventional method, n = 5; original fixed catheter tip method, n = 14; modified fixed catheter tip method, n = 3; and long tapered catheter placement method, n = 3). Of these patients, 10 complained of epigastric discomfort during infusion of the chemotherapeutic drugs, whereas the remaining 15 patients had no clinical symptoms. Twenty-four of these patients were then treated with systemic chemotherapy. Subsequently, progressive disease was seen in 22 of these patients, and effective treatment was achieved in two patients. The remaining one patient, in whom a good response to HAI chemotherapy had been achieved, underwent liver resection. Catheter dislodgment was found in 11 (8.1%) of the 135 patients (conventional method, n = 5; original fixed catheter tip method, n = 3; TABLE 2: Complications, Catheter Dysfunction, and Perfusion Abnormalities Complications Procedure-related complications Conventional Method Side-Hole Catheter Placement Method Original Fixed Modified Fixed Long Tapered Catheter Placement Migration of coil Hematoma around port Thrombosis of axillary artery Complications during HAI chemotherapy Hepatic arterial occlusion Gastroduodenal ulcer Cholangitis Cerebral infarction Catheter dysfunction Catheter dislodgment Occlusion of catheter Catheter kinking near port Perfusion abnormality Development of collateral blood supply to liver Note HAI = hepatic arterial infusion AJR:190, January

6 Seki et al. Proportion Still Receiving Treatment Conventional method modified fixed catheter tip method, n = 1; and long tapered catheter placement method, n = 2). HAI chemotherapy was discontinued in four of these patients, two of whom had catheter dislocation in the abdominal aorta, whereas one patient each had catheter dislocation in the celiac arterial trunk or the splenic artery. These patients then received systemic chemotherapy, which resulted in progressive disease in all four cases. In two patients, the catheter dislodged in the splenic artery and was repositioned successfully after making a pocket surgical opening, and the catheter, which had advanced distally into the right hepatic artery, was hooked and then retracted easily to the proper hepatic artery via a transfemoral approach. In the remaining five patients, HAI chemotherapy could be continued because the side hole of the withdrawn catheter was still within the celiac arterial trunk in three patients and in the common hepatic artery in two patients, although dosage reduction was required in two patients. Cumulative patency rates of the hepatic artery were better in patients treated with the original fixed catheter tip method (6 months, 94.7%; 1 year, 76.3%; 2 years, 66.1%; p = ), the modified fixed catheter tip method (95.0%, 95.0%, 85.5%; p = ), or the long tapered catheter placement method (94.4%, 94.4%, 86.6%; p = ) than the conventional method group (6 months, 51.9%; 1 year, 38.9%). Cumulative catheter stability rates were also higher in patients who were treated with the original fixed catheter tip method (6 months, 100%; 1 year, 96.7%; 2 years, 82.9%; p < ), the modified fixed catheter tip method (95.5%, 95.5%, 95.5%; p = ), or the long tapered catheter placement method (95.2%, 95.2%, 85.7%; p = ) than in patients who received Original fixed catheter tip method Modified fixed catheter tip method Long tapered catheter placement method Time (mo) TABLE 3: Reasons for Discontinuation of Treatment Reasons for Treatment Discontinuation Complications and catheter dysfunctions Conventional Method treatment with the conventional method (6 months, 42.9%; 1 year, 42.9%). Regarding patency of the hepatic artery and catheter stability, there were no statistically significant differences between the side-hole catheter placement methods (hepatic arterial patency, p > 0.17; catheter stability, p > 0.59). Other complications and perfusion abnormalities Gastroduodenal ulcers were seen in two patients and cholangitis in three patients. These patients required temporary interruption of HAI chemotherapy, with dose reduction when the treatment was restarted. Cerebral infarction occurred in three patients, two of whom temporarily developed cerebellar ataxia 3 months after catheter placement, and temporary ophthalmoplegia was observed in one patient after 5 months. These patients were treated conservatively with treatment interruption, and then HAI chemotherapy resumed within a few weeks. Catheter occlusion was seen in one patient, which led to discontinuation of HAI chemotherapy. Kinking of the catheter near the port was observed in two patients, which led to temporary interruption of HAI chemotherapy. These patients underwent surgical opening of the pocket, with the proximal portion of the catheter removed and then reconnected to the port. In 10 patients, intrahepatic perfusion defects were observed on follow-up CT arteriography using the catheter-port system, and the development of a collateral blood supply to the liver was confirmed using angiography via a transfemoral approach. The collateral vessels were embolized to correct the intrahepatic drug distribution in these patients. Side-Hole Catheter Placement Method Original Fixed Modified Fixed Long Tapered Catheter Placement Hepatic arterial occlusion Catheter dislodgment Catheter occlusion Disease progression No response to HAI chemotherapy Regrowth of hepatic lesions Extrahepatic progression Complete response Rejection of treatment continuation Death due to myocardial infarction Note HAI = hepatic arterial infusion. Fig. 2 Graph shows Kaplan-Meier curves for time receiving treatment according to method of catheter placement. Time to treatment discontinuation is significantly longer in patients treated with original or modified fixed catheter tip or long tapered catheter placement methods than in patients treated with conventional method (p < , p = , and p = , respectively, log-rank test). 116 AJR:190, January 2008

7 Side-Hole Catheter Placement for HAI Chemotherapy TABLE 4: Tumor Response Response Tumor response (no.) Conventional Method (n = 10) Time to Treatment Discontinuation Time to treatment discontinuation was significantly longer in patients treated with the original fixed catheter tip method (median, 11.7 months; p < ), the modified fixed catheter tip method (14.4 months; p = ), or the long tapered catheter placement method (12.4 months; p = ) than in patients treated with the conventional method (median, 3.2 months) (Fig. 2). No statistically significant differences were observed among the side-hole catheter placement method groups (p > 0.18). The reasons for treatment discontinuation are summarized in Table 3, which shows that the reasons differed between the groups treated by either the conventional method or the side-hole catheter placement methods. Of the patients treated with the conventional method, 50.0% (five of 10 patients) and 30.0% (three of 10 patients) ceased treatment because of hepatic Side-Hole Catheter Placement Method Original Fixed (n = 77) Modified Fixed (n = 24) Long Tapered Catheter Placement (n = 24) Complete response Partial response Stable disease Progressive disease Objective response rate (%) Proportion Hepatic Progression-Free Conventional method Time (mo) arterial occlusion and catheter dislodgment, respectively, compared with 16.0% (20 of 125 patients; p = ) and 0.8% (one of 125 patients; p = ) of patients treated with one of the side-hole catheter placement methods. Response and Survival The tumor responses are listed in Table 4. Although the objective response rates in the side-hole catheter placement method groups were % compared with 50.0% in the conventional method group, these differences did not reach statistical significance (p > 0.11). However, of the responsive cases treated using the side-hole catheter placement methods, eight patients were able to undergo liver resection, six of whom had no remaining tumors. The median time to hepatic progression was 5.5, 14.7, 15.7, and 15.8 months for patients treated using the conventional, original fixed Original fixed catheter tip method Modified fixed catheter tip method Long tapered catheter placement method Proportion Extrahepatic Progression-Free catheter tip, modified fixed catheter tip, or long tapered catheter placement methods, respectively. Thus, time to hepatic progression was significantly longer in patients who were treated with the original or modified fixed catheter tip or long tapered catheter placement methods than in patients who were treated with the conventional method (p = , , and , respectively; Fig. 3). Extrahepatic progression was analyzed in 88 patients who had isolated liver metastases at initiation of treatment. The median time to extrahepatic progression was 9.6, 10.7, 10.8, and 12.2 months for patients treated with the conventional, original fixed catheter tip, modified fixed catheter tip, and long tapered catheter placement methods, respectively. The time to extrahepatic progression did not differ significantly among the patient groups (p > 0.75; Fig. 4). The median survival time was 13.1, 21.1, 22.5, and 23.1 months for patients treated with the conventional, original fixed catheter tip, modified fixed catheter tip, and long tapered catheter placement methods, respectively. Compared with survival for the conventional method group, overall survival was significantly better for patients treated with the original fixed catheter tip method (p = ), the modified fixed catheter tip method (p = ), or the long tapered catheter placement method (p = ; Fig. 5). No significant differences in survival were observed among the three side-hole catheter placement methods (p > 0.26). Conventional method Original fixed catheter tip method Modified fixed catheter tip method Long tapered catheter placement method Time (mo) Fig. 3 Graph shows Kaplan-Meier curves for hepatic progression according to method of catheter placement. Time to hepatic progression is significantly longer in patients who received treatment with original or modified fixed catheter tip or long tapered catheter placement methods compared with patients who received treatment with conventional method (p = , p = , and p = , respectively, log-rank test). Fig. 4 Graph shows Kaplan-Meier curves for extrahepatic progression according to method of catheter placement. No significant difference is noted among four groups (p > 0.75, log-rank test). AJR:190, January

8 Seki et al. Proportion Surviving Discussion Our study results show a positive correlation between the use of side-hole catheter placement methods and improvement in survival of patients treated with HAI chemotherapy for unresectable liver metastases from colorectal cancer. Previous studies have described catheter dislodgment and hepatic arterial occlusion as major complications that can accompany radiologic catheter implantation using the conventional method. These complications can lead to a temporary or even permanent interruption of HAI chemotherapy [16 18]. To resolve these problems, side-hole catheter placement methods have been developed, such as the fixed catheter tip and the long tapered catheter placement methods [19 23]. In these methods, fixation of the catheter tip and catheter insertion distally into the hepatic artery contribute to reduced mobility of the catheter and to diminished mechanical stimulation of the hepatic arterial wall, resulting in decreased risk of catheter dislodgment and hepatic arterial occlusion. Indeed, our study results show significantly higher catheter stability rates and hepatic artery patency rates in patients treated with side-hole catheter placement methods than in those treated with the conventional method. As a result, time to treatment discontinuation was significantly longer in patients treated with side-hole catheter placement methods than in those treated with the conventional method. Long-term administration of HAI chemotherapy appeared to be associated with an enhanced time to hepatic progression, observed in patients treated with side-hole catheter placement methods. However, prolonged HAI chemotherapy was not associated with prevention of extrahepatic metastatic progression. Conventional method Original fixed catheter tip method Modified fixed catheter tip method Long tapered catheter placement method Time (mo) Fig. 5 Graph shows Kaplan-Meier curves for overall survival according to method of catheter placement. Overall survival is significantly better in patients treated with original or modified fixed catheter tip or with long tapered catheter placement method compared with patients treated with conventional method (p = , p = , and p = , respectively, log-rank test). Moreover, our study found that overall survival was significantly longer in patients treated with side-hole catheter placement methods than in patients treated with the conventional method. These results indicate that the use of side-hole catheter placement methods instead of the conventional method for HAI chemotherapy enhanced treatment efficacy with a decreased frequency of catheter-related complications and increased survival due to improved longterm control of the hepatic tumors. The differences in survival that we observed in our study may have been attributable to other factors, including patient characteristics. However, we found no statistically significant difference in variables that appeared to affect prognosis, such as a patient s performance status and percentage of liver involvement, between patients treated by either the conventional method or one of the side-hole catheter placement methods. Of these variables, the coexistence of extrahepatic lesions at the initiation of treatment was relatively different, although this difference was not statistically significant. The coexistence of extrahepatic lesions was seen more frequently in patients treated with sidehole catheter placement methods than in patients treated with the conventional method. Nevertheless, time to hepatic progression and overall survival were significantly longer in the groups treated with one of the side-hole catheter placement methods than the conventional method group. Therefore, we believe that the use of side-hole catheter placement methods rather than the conventional method contributed not only to a decrease in complications, but also to improved survival and long-term control of hepatic lesions. Regarding treatment outcome, no significant differences were observed among the three sidehole catheter placement methods used in our study. Comparison of the original fixed catheter tip method that used a 5-French catheter with the modified method that used a catheter with a 2.7-French distal shaft showed no significant differences in the time to treatment discontinuation, time to hepatic progression, or survival. It is possible that when the catheter tip is fixed within the gastroduodenal artery, the caliber of the implanted catheter may not be important for the long-term use of the catheter-port system. When the gastroduodenal artery is absent due to previous surgery or anatomic anomalies of the hepatic artery, the fixed catheter tip method cannot be used for catheter implantation. However, the long tapered catheter placement method can still be used in these cases [23]. In our study, after the introduction of the long tapered catheter, this method of placement was used in such cases rather than the conventional method. In addition, treatment efficacy of the long tapered catheter placement method was almost equal to that of the fixed catheter tip method. Radiologic catheter implantation can therefore be achieved safely and effectively in most cases by using either the fixed catheter tip method or the long tapered catheter placement method. Several randomized studies have compared HAI chemotherapy with systemic chemotherapy [5 14]. Almost all of those studies showed an increased response rate with HAI chemotherapy, although this superior response rate did not translate into greater survival benefit. Most of these earlier trials, however, included relatively small numbers of patients, and several studies also allowed crossover to HAI chemotherapy at the time of progression of systemic therapy, a change that may have diluted the statistical results and may have been measured as an improvement in survival. Moreover, in two recent 118 AJR:190, January 2008

9 Side-Hole Catheter Placement for HAI Chemotherapy trials in Europe [12, 13], a high frequency of catheter-related problems occurred in patients who had been allocated to the HAI chemotherapy treatment arm, resulting in treatment failures and no survival benefit. The Medical Research Council (MRC) and the European Organization for the Research and Treatment of Cancer (EORTC) groups [13] compared HAI chemotherapy with systemic chemotherapy in 290 randomized patients, with both 5-FU and LV being used. In that study, 34% of patients assigned to the HAI chemotherapy arm did not receive treatment and 29% had to stop treatment because of catheter-related problems. As a result, no differences were noted between the HAI chemotherapy arm and the systemic chemotherapy arm not only in progression-free survival (median, 7.7 and 6.7 months, respectively) or overall survival (14.7 and 14.8 months, respectively), but also in tumor response rate (22% and 19%, respectively). Lurenz and Müller [12] randomized 168 patients to HAI chemotherapy with fluorodeoxyuridine (FUDR), HAI chemotherapy with 5-FU and LV, or systemic therapy with 5-FU and LV. In that trial, 31% of the patients in the HAI chemotherapy arms did not receive the assigned treatment due to the detection of extrahepatic disease, infeasibility of catheter implantation, or postoperative complications, and HAI chemotherapy had to be terminated in 25% of the patients due to catheter-related complications or catheter dysfunction. No difference in survival was seen between the HAI chemotherapy arms and the systemic chemotherapy arm (medians, 12.7 months in HAI chemotherapy of FUDR and 18.7 months in HAI chemotherapy of 5-FU and LV vs 17.6 months in systemic chemotherapy of 5-FU and LV). On the other hand, the Cancer and Leukemia Group B (CALGB) trial [14] recently reported a comparison of HAI chemotherapy of FUDR, dexamethasone, and LV with systemic chemotherapy of 5-FU and LV in 135 randomized patients. In that study, no crossover was permitted. The HAI chemotherapy group had a significant increase in survival compared with the systemic group (median, 24.4 vs 20.0 months, respectively; p = ). In that CALGB trial, the actual number of patients treated with HAI chemotherapy was 87%, compared with only 66% in the MRC/EORTC study [13] and 69% in the German study [12]. This difference appears to contribute to improved survival of HAI chemotherapy over systemic chemotherapy. To allow proper evaluation of the survival benefit of HAI chemotherapy, we believe that it is important to use adequate catheter-port systems that permit the successful implantation and the long-term administration of intrahepatic chemotherapy. In previous studies, catheterrelated complications or device malfunctions have been reported in up to approximately 30% of patients [16, 30]. In agreement with previous investigators and also our experience, hepatic arterial occlusion and catheter dislodgment are the predominant complications of HAI chemotherapy. Our study results reveal that side-hole catheter placement methods were useful for long-term treatment due to the prevention of hepatic arterial occlusion and catheter dislodgment, which then contributed to improved survival. We therefore propose that side-hole catheter placement methods should be used when evaluating the clinical value of HAI chemotherapy. The other observation drawn from the trials of HAI chemotherapy has been that despite better control of liver metastases, the rate of development of extrahepatic metastases has generally been higher than that seen with systemic treatment [5 14]. In our study, although the time to extrahepatic progression was not improved even using the side-hole catheter placement methods, the time to hepatic progression was prolonged. Insufficient control of extrahepatic metastases may be the other reason for the only marginal survival benefit associated with HAI chemotherapy. Recently, a superior response and survival were shown with systemic treatment of irinotecan- and oxaliplatin-based regimens in patients with metastatic colorectal cancer [3, 4]. Using these new therapies, combinations of HAI chemotherapy with new chemotherapeutic agents are currently being investigated to improve the control of extrahepatic disease and achieve good responses against hepatic lesions. Kemeny et al. [31] reported a trial using systemic oxaliplatin plus irinotecan or oxaliplatin plus 5-FU and LV with concurrent HAI chemotherapy of FUDR and dexamethasone, which produced time to extrahepatic progression of 16.9 and 9.4 months, respectively, and median overall survival of 35.8 and 22 months. These results suggest that combinations of HAI chemotherapy with systemic administration of new agents may enhance survival more than either HAI chemotherapy alone or systemic therapy alone. On the other hand, HAI chemotherapy based therapy in patients refractory to systemic chemotherapy has produced excellent response rates. Several trials using HAI chemotherapy of FUDR combined with systemic irinotecan, oxaliplatin, or both in patients previously treated systemically, including irinotecan, reported response rates ranging from 74% to 90% [31, 32]. Hepatic arterial infusion of oxaliplatin with IV or intraarterial infusion of 5-FU and LV has also been investigated in previously treated patients, and patients showed response rates ranging from 24% to 64% and median survival times ranging from 18.3 to 36.1 months [33 35]. These studies indicated that combinations of HAI chemotherapy with systemic therapy may also be promising in the secondline setting. However, in some of these current trials, catheter-related problems still occurred frequently, resulting in treatment discontinuation [33, 34]. We think that to extend the benefit of HAI chemotherapy it is necessary not only to investigate combinations of new agents, but also to use catheter-port systems suitable for long-term use. We recognize some limitations of our study. This study was a retrospective analysis. In addition, in our study there was no uniform criterion for deciding the method of catheter placement. At first, the original fixed catheter tip method was used. Later, this method was replaced by the modified fixed catheter tip and long tapered catheter placement methods. The latter method has become the preferred one recently. The conventional method was used during the first half of the study for patients who were unable or unwilling to undergo fixed catheter tip placement. As a result, there were only 10 patients in the conventional method group compared with a range of patients in the groups using sidehole catheter placement methods. This small sample size lowers the statistical power of the study and may also have influenced the comparative statistical analyses. Therefore, the results of this retrospective study need to be confirmed by a prospective, randomized trial that directly compares the conventional and side-hole catheter placement methods. In conclusion, radiologic catheter implantation using side-hole catheter placement methods rather than the conventional method appears to be useful for the delivery of long-term intrahepatic chemotherapy and leads to enhanced survival of patients with unresectable liver metastases from colorectal cancer. The question as to whether HAI chemotherapy using effective catheter placement methods can better enhance survival when used alone or in combination with systemic treatment needs to be addressed in future studies. References 1. Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: im- AJR:190, January