1549 Limited but Definite Efficacy of Prophylactic Hepatic Arterial Infusion Chemotherapy after Curative Resection of Colorectal Liver Metastases A Randomized Study Takeshi Tono, M.D., Ph.D.1,2 Yasunori Hasuike, M.D., Ph.D.1 Hiroki Ohzato, M.D., Ph.D.2 Yuichi Takatsuka, M.D., Ph.D.2 Nobuteru Kikkawa, M.D., Ph.D.1 1 Department of Surgery, Osaka National Hospital, Osaka, Japan. 2 Department of Surgery, Kansai Rosai Hospital, Hyogo, Japan. Supported in part by a grand-in-aid for cancer research from the Ministry of Health and Welfare (6-17), Japan. The authors are grateful to Yuika Kanaishi, Ph.D., for her help in preparing the article. Address for reprints: Takeshi Tono, M.D., Ph.D., Department of Surgery, NTT West Osaka Hospital, 2-6-40 Karasugatsuji, Tennoji-ku, Osaka, Osaka 543-8922, Japan. Received February 17, 1999; revisions received July 16, 1999, and November 29, 1999; accepted November 29, 1999. © 2000 American Cancer Society BACKGROUND. Greater than 50% of patients who undergo curative resection of liver metastases from colorectal carcinoma develop recurrent disease in the residual liver. Although several studies have attempted to use hepatic arterial infusion (HAI) chemotherapy to prevent recurrence, to the authors’ knowledge the efficacy of the treatment has not yet been determined. METHODS. Nineteen patients who underwent curative hepatectomy for metastatic colorectal carcinoma randomly were assigned into the HAI group (nine patients) or the control group (ten patients). Patients in the HAI group received continuous intraarterial infusion of 5-fluorouracil (5-FU) (500 mg/day) for 4 days followed by a 3-day rest. The treatment was continued for 6 weeks. RESULTS. The median follow-up period was 62.2 months. The recurrence was confirmed in three patients in the HAI group and in eight patients in the control group. Of these, recurrence in the remnant liver was observed in one patient and in six patients, respectively. The median disease free interval after hepatectomy was 62.6 months in the HAI group and 13.8 months in the control group. The 1-year, 2-year, and 3-year disease free survival rates were 77.8%, 77.8%, and 66.7%, respectively, in the HAI group and 50.0%, 30.0%, and 20.0%, respectively, in the control group. Significant prolongation of disease free survival was observed in the HAI group (P ⫽ 0.045). No patients in the HAI group reported any adverse effect of ⱖ Grade 2 (according to the National Cancer Institute Common Toxicity Criteria). Two patients in the HAI group and five patients in the control group were dead of disease at the time of last follow-up. The 1-year, 3-year, and 5-year cumulative survival rates for the HAI group were 88.9%, 77.8%, and 77.8%, respectively, whereas those of the control group were 100.0%, 50.0%, and 50.0%, respectively (P ⫽ 0.2686). CONCLUSIONS. This randomized study revealed that short term HAI of 5-FU after curative resection of colorectal hepatic metastases is effective in preventing the recurrence of disease without any serious complications. Cancer 2000;88:1549 –56. © 2000 American Cancer Society. KEYWORDS: colorectal carcinoma, liver metastases, adjuvant chemotherapy, hepatic arterial infusion, 5-fluorouracil, fluoropyrimidines, curative resection, regional chemotherapy, randomized study. H epatic resection is potentially regarded as the only curative treatment for liver metastases originating from colorectal carcinoma, and the 5-year survival rate after hepatectomy has been reported to range from 25– 45%.1–5 However, approximately 60 –75% of patients 1550 CANCER April 1, 2000 / Volume 88 / Number 7 develop recurrent disease after curative tumor resection and ⬎ 50% develop recurrent lesions in the residual liver.1–5 Fluoropyrimidines have been known as one of the most effective chemotherapeutic agents against colorectal carcinoma6 and are widely used for postoperative adjuvant chemotherapy via a systemic route.7,8 In addition, fluoropyrimidines have been administered locally through the hepatic artery against unresectable liver metastases, and a high response rate has been reported.9 –14 Recently, several trials of hepatic arterial infusion (HAI) of fluoropyrimidines as adjuvant local chemotherapy after curative hepatectomy have been performed.15–25 However, to our knowledge few reports discussed its long term outcomes compared with control treatment. It remains uncertain whether HAI is beneficial in the prevention of recurrent disease. We investigated the efficacy of 5-fluorouracil (5-FU) HAI as prophylactic regional chemotherapy after curative resection of colorectal liver metastases using a prospective randomized study. MATERIALS AND METHODS From February 1993 to March 1995, 23 patients with liver metastases from colorectal primary tumors underwent hepatic resection at Osaka National Hospital. Of these patients, 19 age ⬍ 75 years with curative resection and no serious preoperative complications were entered into the study to evaluate HAI with 5-FU as postoperative adjuvant chemotherapy after hepatectomy. Four patients were ineligible due to noncurative hepatectomy in 2 cases and age ⬎ 75 years in 2 cases. The protocol was approved by the Osaka National Hospital Institution Review Board. Patients randomly were assigned treatment intraoperatively just after curative hepatectomy was performed. The randomization was performed by cards in envelopes from a box that were supplied by an independent institute. There was no scheme of randomization. Each patient approved an informed consent form prior to surgery. Nineteen patients were assigned into an HAI group (9 patients) and a control group (10 patients). Surgical Evaluation/Treatment The liver metastases were removed either by anatomic or nonanatomic hepatic resection according to the tumor status (number, size, and location). In all patients, prophylactic cholecystectomy was performed and intraoperative ultrasonography (US) was performed to confirm the status of the tumors, to identify the exact anatomy of the liver in relation to the tumors, and to determine the transection line of hepatic parenchyma. Surgery was considered curative when all detectable tumors were removed with ⬎ 1 cm of surgical margin. Pathologic examination also was performed to confirm the diagnosis and the negative surgical margin. In the HAI group, a catheter (Infuse-APort, Horizon Medical Products, Inc., Manchester, GA) was inserted from the gastroduodenal artery and the tip of the catheter was located at the junction of the gastroduodenal artery and the hepatic artery. A port connected to the catheter then was implanted subcutaneously in the right upper abdomen. In one case of dual hepatic arterial supply, the right hepatic artery arising from the superior mesenteric artery was ligated and the catheter placed in the remaining artery. Adequacy of perfusion was confirmed intraoperatively with infusion of diluted indigo carmine and postoperatively with enhanced computed tomography (CT) through the port. Chemotherapy HAI was started on the fourteenth postoperative day or when serum glutamic oxaloacetic transaminase (aspartate aminotransferase) fell to less than three times normal. Two thousand milligrams of 5-FU diluted with 20 mL of normal saline and 1000 u of heparin were filled into a Baxter Infusor Multiday Type (Baxter Healthcare Inc., Deerfield, IL) and infused at 0.5 mL/ hour (500 mg of 5-FU/day). Normally the chemotherapy was performed from Monday through Friday (96hour continuous infusion) followed by a 3-day rest, which was defined as 1 cycle. The patients could go about their daily lives in a nearly normal with the external infusion pump because when filled with agents the pump weighs as little as 125 g even on the starting day. Six cycles of chemotherapy were administered to each patient. All treatment was performed on an outpatient basis. Treatment was held or discontinued for any toxicities greater than Grade 2 including hematologic, gastrointestinal, neurologic, cutaneous, renal, and hepatic toxicities. Toxicities were classified using 1991/ 1992 National Cancer Institute Common Toxicity Criteria (National Cancer Institute, Bethesda, MD). The patients assigned to the control group received 200 mg/day of oral 5-FU from postoperative Day 14 for 2 years. All patients who had completed HAI also were administered the identical dose of oral 5-FU for the same period. Follow-Up All patients were followed at our institute and postoperative examinations were performed periodically according to the following schedule. Liver function tests as well as blood cell counts were conducted every week during HAI therapy and every 3 months in the Adjuvant Regional Chemotherapy for Colorectal Liver Metatstases/Tono et al. 1551 TABLE 1 Patient Demographic Data Age (mean ⫾ SD) Gender (M/F) Dukes Stage (B/C) Tumor size (mm) (mean ⫾ SD) Chronology (synchronous/metachronous) No. of tumor (solitary/multiple) Location (unilobar/bilobar) Type of hepatectomy (anatomical/nonantomic) HAI group (n ⴝ 9) Control group (n ⴝ 10) P value 59.0 ⫾ 5.8 5/4 2/7 26.3 ⫾ 14.9 4/5 3/6 5/4 5/4 61.9 ⫾ 5.0 6/4 3/7 19.3 ⫾ 8.6 6/4 7/3 8/2 4/6 0.0887 0.8447 ⬎ 0.9999 0.2189 0.8087 0.1547 0.4988 ⬎ 0.9999 HAI: hepatic arterial infusion; SD: standard deviation; M: male; F: female. later course. Tumor markers including carcinoembryonic antigen and carbohydrate antigen 19-9 were measured every 3 months. Hepatic US and/or CT scan were performed every 3 months up to 2 years after hepatectomy and every 6 months thereafter. Chest X-ray films were examined every 6 months and chest CT scan was performed once a year. Pelvic or abdominal CT scans also were examined periodically in patients with locally advanced disease. Statistical Analysis The survival curve was obtained by the Kaplan–Meier method and comparisons between groups were performed by the log rank test. The distribution of patient characteristics in the two groups was examined by the chi-square test. The comparison of the mean value was performed by the Student t test. The level of statistical significance was P ⬍ 0.05. RESULTS Patient Characteristics There were five males and four females in the HAI group and six males and four females in the control group (Table 1). The mean ages in each group were 59.0 ⫾ 5.8 years (mean ⫾ standard deviation) and 61.9 ⫾ 5.0 years, respectively. In terms of Dukes Stage for the original carcinoma, two of nine cases were Stage B and the remaining seven were Stage C in the HAI group, whereas three of ten cases were Stage B and seven were Stage C in the control group. The average greatest tumor dimension in the HAI group was 26.3 ⫾ 14.9 mm, and that of the control group was 19.3 ⫾ 8.6 mm. Synchronous metastases were found in 44.4% of the patients in the HAI group and 60.0% of the patients in the control group. Three patients in the HAI group had solitary tumors whereas seven of ten patients in the control group had a single metastasis in the liver. In the HAI group, metastatic lesions were observed in a unilateral lobe of the liver in five pa- tients and in bilateral lobes in four patients. In the control group, eight patients had unilobar tumors and two had bilobar lesions. With regard to surgical procedures, anatomic hepatic resection was performed in 55.6% of the patients in the HAI group and nonanatomic (wedge) resection was performed in the remaining 44.4% of patients. Conversely, in the control group, 40.0% of patients underwent anatomic resection and the remaining 60.0% underwent nonanatomic hepatectomy. None of these findings were regarded as statistically significant between the two groups. Toxicity Only one patient of nine who received regional chemotherapy developed Grade 1 nausea and anorexia, which were endurable. No patients had hematologic toxicity, hepatitis, sclerosing cholangitis, or complications related to the implantable port system. Thus all nine patients were completely able to receive HAI chemotherapy for 6 weeks on schedule. Based on hepatic CT scans examined 3 months after surgery, HAI chemotherapy did not affect the regenerative capacity of the residual liver. There were no apparent adverse effects with regard to the oral administration of 5-FU. Recurrence of Disease All 19 patients enrolled in the current study were evaluable. The range of follow-up was between 49.5– 70.0 months, and the median follow-up was 62.2 months. Disease recurrence was observed in 8 patients (80.0%) in the control group and in 3 patients (33.3%) in the HAI group. Six of eight patients in the control group who developed disease recurrence had recurrent tumors in the residual liver, whereas one patient of three in the HAI group was found to have recurrent lesions in the liver. Among five patients in the control group who had recurrent tumors only in the liver, three underwent a 1552 CANCER April 1, 2000 / Volume 88 / Number 7 FIGURE 1. Disease free survival after hepatectomy. Solid line: hepatic arterial infusion group (n ⫽ 9); dashed line: control group (n ⫽ 10). FIGURE 2. Cumulative survival after hepatectomy. Solid line: hepatic arterial infusion group (n ⫽ 9); dashed line: control group (n ⫽ 10). second hepatectomy. The remaining two patients and one patient with both intrahepatic and extrahepatic disease received regional chemotherapy. The other two patients with extrahepatic recurrence in the control group received systemic chemotherapy. Conversely, of the three patients with recurrent disease in the HAI group, one underwent a repeat hepatectomy, one underwent resection of lung metastases, and the remaining patient received systemic chemotherapy. plained from the concepts of “first pass effect” and “increased local concentration.”26 Because fluoropyrimidines have high rate of first-pass hepatic extraction, a high concentration of the drug in the liver with limited systemic exposure is obtained with HAI of fluoropyrimidines.26 –28 The advantage of hepatic arterial delivery of fluoropyrimidines also is understood from its increased local concentration without the first-pass effect calculated from the ratio of total body clearance of the drug.29 Colorectal liver metastases derive their blood supply almost exclusively from the hepatic artery, whereas normal hepatic parenchyma is perfused both by the portal vein and the hepatic artery.30 These findings encourage physicians to perform HAI chemotherapy with fluoropyrimidines for the treatment of liver metastases from colorectal primary tumors. Several significant attempts to use HAI as adjuvant chemotherapy after hepatectomy have been performed and a decreased disease recurrence rate in the remnant liver has been reported (Table 2).15–23 However, the majority of the studies did not include the appropriate control treatment or the follow-up period was not long enough to evaluate the efficacy of prophylactic regional chemotherapy. Thus our prospective randomized study was designed to determine whether HAI chemotherapy after curative resection of colorectal liver metastases is beneficial. Our trial, with ⬎ 5 years of observation, revealed that the disease free survival of patients who received HAI was significantly higher than that of the control group (P ⫽ 0.045). This result is consistent with two previous reports of randomized trials of adjuvant HAI chemotherapy, although the number of patients or the length of the follow-up period did not appear ideal in those stud- Survival The median disease free interval after hepatectomy was 62.6 months (range, 5.1–70 months) in the HAI group and 13.8 months (range, 4.5– 60.5 months) in the control group. The 1-, 2-, and 3-year disease free survival rates in the control group were 50.0%, 30.0%, and 20.0%, respectively, whereas those of the HAI group were 77.8%, 77.8%, and 66.7%, respectively (Fig. 1). The difference between the groups was regarded as statistically significant (P ⫽ 0.045). Two patients in the HAI group and five patients in the control group were dead of disease at last followup. The median survival time of the HAI group was 62.6 months (range, 11.2–70.0 months) and that of the control group was 39.9 months (range, 20.4 – 60.5 months). The 1-, 3-, and 5-year cumulative survival rates in the HAI group were 88.9%, 77.8%, and 77.8%, respectively, and 100.0%, 50.0%, and 50.0%, respectively, in the control group (Fig. 2). No significant difference was found between the cumulative survival of the two treatment groups (P ⫽ 0.2686). DISCUSSION The advantage of local arterial chemotherapy compared with systemic therapy is pharmacologically ex- Adjuvant Regional Chemotherapy for Colorectal Liver Metatstases/Tono et al. 1553 TABLE 2 Reported Studies of Prophylactic HAI Chemotherapy after Curative Resection of Colorectal Carcinoma Metastatic to the Liver Authors Year No. of patients Device Agents Period of HAI Control Outcomes Complications Patt et al.15 1987 20 NP FUDR, MMC 16 weeks No MST: 51 mos, LR: 35% Wagman et al.16 1990 11 IP FUDR 12 mos Rand Moriya et al.17 Curley et al.18 Kemeney et al.19 Lygidakis et al.20 Okuno et al.21 Nonami et al.22 Lorenz et al.23 Current series 1991 1993 1993 1995 1996 1997 1998 16 18 8 38 18 31 226 19 EP EP IP IP EP EP EP EP 5-FU, MMC, oral HCFU 5-FU FUDR, iv 5-FU, iv LV 5-FU, MMC, ␣IFN, IL-2 etc. 5-FU, MMC, IL-2 5-FU, MMC, ADM 5-FU, FA 5-FU 6 mos 6 mos 6 mos 3 yrs 6 mos 12 mos 6 mos 6 weeks No No No Rand Hist Hist Rand Rand MDFST: 30.7 mos vs. 8.7 mos (P ⫽ 0.03) LR: 31% MST: 33 mos, LR: 17% MST: 23 mos, LR: 0% MST: 20 mos vs. 11 mos (P ⬍ 0.001) MST: 36.5 mos, LR: 0% vs. 50% 5-yr SR: 57% vs. 10% (P ⬍ 0.05) MDFST: 21.6 mos vs. 24 mosa 5-yr DFSR: 66.7% vs. 20% (P ⫽ 0.045) Hepatitis: 70%, peptic ulcer: 23% Dead of complications: 40% Hepatitis: 19%, cholangitis: 19% Cessation of HAI: 44% Hepatitis: 50% Granulopenia 16%, fever 100% Cholangitis: 6%, fever 100% Peptic ulcer: 3% 30-day death: 7.5% None HAI: hepatic arterial infusion; NP: no port implanted; FUDR: floxuridine; Rand: randomized study; MMC: mitomycin C; MST: median survival time; LR: liver recurrence rate; IP: implanted pump; MDFST: median disease free survival time; EP: external pump with implanted port; 5-FU: 5-fluorouracil; HCFU: 1-hexycarbamoyl-5-fluorouracil; iv: intravenous; LV: leucovorin; ␣IFN: ␣-interferon; IL-2; interleukin 2; Hist: historic control; ADM: doxorubicin; SR: survival rate; FA: folinic acid; DFSR: disease free survival rate. a Depends on the subject of each analysis; data will be altered to 44.8 mos versus 23.3 mos. ies.16,20 Recently Lorenz et al. reported that a decreased recurrence rate was not obtained with postoperative adjuvant HAI therapy in a randomized trial with large number of patients.23 However, in the study only 74% of the patients assigned to the HAI group received the therapy. The median disease free survival time was nearly doubled (44.8 months vs. 23.3 months) when analysis was performed in patients actually treated. It has been reported that several prognostic factors such as Dukes stage, tumor size, chronology, the number of tumors, and others may relate to the outcome after curative hepatectomy of metastatic colorectal carcinoma.1–5 It might be difficult to deny that some differences in patient background factors between the HAI and control groups in the current series could have affected the outcome of the randomized trial because the number of patients entered is relatively small. However, no significant difference was observed between the two groups, and the majority of those factors were even favorable in the control group, which showed a lower survival rate (Table 1). In terms of the duration of adjuvant regional chemotherapy, many investigators continued HAI for ⱖ 6 months after hepatectomy.16 –23 The period of prophylactic HAI in the current trial was only 6 weeks and the total dosage of 5-FU administered intraarterially was as low as 12 g. Some may ask whether such an amount of 5-FU could be potent enough to suppress recurrence of the disease. However, the majority of hepatic recurrences after curative resection of liver metastases arise from subclinical or microscopic lesions in the remnant liver, which are the targets of adjuvant HAI therapy. There is a report that regional infusion of an amount of 5-FU similar to that used in the current decreased the recurrence rate compared with the historic control.31 It is known that the hepatic extraction rate of floxuridine (FUDR) is higher than 5-FU, and FUDR has been regarded as the best drug for HAI chemotherapy.32 However, 5-FU still is pharmacologically superior to agents other than fluoropyrimidines for HAI therapy.26,28,29 Several reports have demonstrated that HAI of 5-FU in patients with unresectable liver metastases showed a response rate of 50 –75%,33–35 which is similar to the result observed with HAI using FUDR.9 –14 A major problem of HAI chemotherapy is the high rate of incidence of toxicities and complications related to the therapy. Kemeney reported that 6 –25% of patients with unresectable metastases who received HAI of FUDR developed serious hepatobiliary toxicities such as sclerosing cholangitis, which often is fatal.36 Frequent hepatobiliary toxicity also was observed in patients treated with prophylactic HAI of FUDR.15,16,19 Wagman et al. reported two of five patients treated with prophylactic HAI of FUDR died of hepatobiliary toxicities,16 which appears to be an unacceptable event because the patients had received adjuvant therapy after curative surgery. In contrast, 5-FU is recognized as less toxic, especially to the hepatobiliary tract,37,38 and low levels of toxicities were reported in patients treated with prophylactic HAI of 5-FU.18,21,22 In the current series only one patient reported Grade 1 gastrointestinal symptoms, and no 1554 CANCER April 1, 2000 / Volume 88 / Number 7 other adverse effects were observed throughout the therapy. Conversely, some reports pointed out that HAI of 5-FU often resulted in arteritis or hepatic arterial thrombosis.35,36,39 Curley et al. reported that arteritis, arterial thrombosis, and irreversible port or catheter occlusion occurred in 2, 1, and 3 patients, respectively, of 18 patients who received adjuvant HAI (10-minute injection) of 5-FU for 24 weeks, and chemotherapy had to be discontinued in those instances.18 In the current study there was no apparent complication in 9 patients who received 24-hour infusion of 5-FU for 6 weeks with 4 days of administration and 3 days of rest. Of course we cannot ignore the possibility of subclinical events such as hepatic arterial stenosis, because detailed examinations including angiography were not performed after termination of HAI. However, liver function tests remained normal throughout the therapy period, and no patients reported fever or abdominal pain. We speculate the reason why no serious complication was observed in the current trial was due simply to the short duration of infusion therapy. There might be an opinion that the device used in this study, an implanted small port with external infusion pump, is suboptimal. Indeed the totally implantable pump used by many researchers has many beneficial aspects.40,41 However, the device is very expensive and removal of the whole system is nearly impossible. In our protocol, the patients could maintain a fairly satisfactory quality of daily life because the external pump used was very small and lightweight. The period of chemotherapy was so short (6 weeks) that few patients complained about the inconvenience related to the treatment. Furthermore, in recent patients receiving prophylactic regional chemotherapy, we have placed a catheter by a percutaneous method through the femoral or subclavian artery.42 Thus the catheter as well as the port can be removed easily whenever adjuvant chemotherapy is completed and no further treatment is regarded as needed. It is not surprising that there was no significant difference in the cumulative survival rate between the HAI and control groups despite the disease free survival being significantly higher in the HAI group. First, the significance of aggressive surgical treatment including repeated hepatectomy for recurrent disease after first resection of colorectal liver metastases has been well established.43– 45 Four patients with recurrent hepatic lesions in the current study underwent second resection of the liver, which could affect the outcome of overall survival. Furthermore, the existence of extrahepatic disease recurrence also plays a critical role in determining the result after curative resection of liver metastases from colorectal primary tumors. Thus development of effective combined protocols of HAI and systemic chemotherapy is required if physicians wish to obtain a survival benefit from adjuvant chemotherapy after curative hepatectomy of colorectal liver metastases. From the viewpoint of prophylactic chemotherapy, approaches different from the treatment of patients with unresectable metastases are needed. Nearly 50% of the patients who undergo curative resection of colorectal liver metastases have no further disease, at least in the remnant liver.1–5 Therefore, we need to adopt a treatment regimen with a minimal possibility of serious adverse effects. Patients should be released from the hospital and free from intensive treatment at an early phase after surgery. 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