Japanese Journal of Clinical Oncology 33:132-135 (2003)
© 2003 Foundation for Promotion of Cancer Research
Weekly Hepatic Arterial Infusion of 5-Fluorouracil and Subsequent Systemic Chemotherapy for Liver Metastases from Colorectal Cancer
1 Gastrointestinal Oncology Division and 2 Colorectal Surgery Division, National Cancer Center Hospital, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: To determine the antitumor activity and toxicity of weekly hepatic arterial infusion (HAI) of 5-fluorouracil (5-FU) for liver metastases from colorectal cancer. In addition, the present study also evaluated the efficacy of second-line chemotherapy after termination of HAI.
Methods: A retrospective study was designed to evaluate the clinical outcome in patients treated with HAI. Twenty-six patients with liver metastases from colorectal cancer were treated with 5-FU 1000 mg/m2 over 5 h once per week on an outpatient basis. The treatment was continued until disease progression, unacceptable toxicity or the patient’s refusal to continue treatment occurred. One of three kinds of second-line systemic chemotherapy, irinotecan alone, protracted venous infusion of 5-FU or methotrexate (MTX) and 5-FU, was chosen after termination of HAI.
Results: An objective tumor response to HAI was observed in 46% (95% confidence interval, 26.9–65.2%) of 26 patients. The most common adverse events were mild nausea and vomiting (35%) and occurrence of gastroduodenal ulcers (15%). Hematological toxicity was minimal. No responder was observed to improve following second-line chemotherapy after termination of HAI.
Conclusion: Weekly HAI of 5-FU is both active and well tolerated. However, extrahepatic progression was observed in one-third of patients with termination of HAI and the efficacy of second-line chemotherapy was not demonstrated. Regional treatment with systemic chemotherapy should be conducted to achieve good results in terms of survival.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Hepatic metastases are the most common visceral metastases from colorectal carcinoma and are observed in 18% of patients on initial diagnosis of their primary tumor and will occur in 60% of patients who subsequently develop advanced disease (1). Although hepatic resection is the only potentially curative treatment, the value of which has been proven with a 5-year survival rate of 25–35% (2), curative resection of liver metastases is possible in less than 25% (3).
For unresectable lesions, systemic 5-fluorouracil (5-FU) therapy is marginally active in prolongation of survival. The rationale for hepatic arterial infusion (HAI) is as follows. The normal liver has a dual blood supply. Liver metastases obtain most of their blood supply from the hepatic artery, whereas normal liver cells derive most of their blood supply from the portal vein (4). Hence direct hepatic arterial infusion increases drug concentrations at the tumor site, and at the same time decreases systemic drug exposure (5).
Prospective, randomized studies of patients with unresectable liver disease have reported response rates from 42 to 62% in the group given HAI, compared with rates of 10–21% in the groups treated with systemic chemotherapy (6–11). It is therefore common practice in Japan to perform continuous arterial infusion of 5-FU, because the response rate of HAI is significantly higher than that of systemic chemotherapy. An encouraging result was obtained from a phase II clinical trial of intermittent HAI with high-dose 5-FU (12), which demonstrated a response rate of 78% and a survival time of 25.8 months without any serious toxicities.
There have been few reports about the impact of second-line systemic chemotherapy in patients refractory to HAI. Hence the role of second-line chemotherapy is still unclear.
The objectives of this study were to evaluate the antitumor activity and toxicity of weekly HAI of 5-FU for liver metastases from colorectal cancer and the efficacy of second-line chemotherapy after HAI.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Eligibility
Patients with liver metastases from colorectal carcinomas were eligible for this retrospective study if they had histologically confirmed and resected primary colorectal carcinoma, had at least one measurable lesion, had not had prior chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2. Further entry criteria were adequate hepatic function (serum total bilirubin
2 mg/dl), adequate hematological function (white blood cells 
4000/mm3, platelets 100 000/mm3) and adequate renal function (serum creatinine 1.5 mg/dl). Written informed consent was obtained from all patients.
Treatment
A catheter was inserted into the hepatic artery via the subclavian artery for patients with metachronous metastases and into the gastroduodenal artery at the time of resection of the primary site for patients with synchronous metastases. The proximal end of the catheter was connected to an implanted port system. 5-FU was administered at a dose of 1000 mg/m2 over 5 h once per week on an outpatient basis and this treatment was continued until the occurrence of disease progression, unacceptable toxicity or the patient’s refusal to continue treatment. In all patients, gastrointestinal vessels were occluded with steel coils or ligated to preclude gastrointestinal tract perfusion. In addition, we confirmed the hepatic distribution of the drug and checked for the absence of extrahepatic perfusion using angiography by the port before HAI.
Second-line Systemic Chemotherapy
In 17 (74%) patients who terminated HAI, systemic chemotherapy was performed. For patients refractory to HAI, we mainly administered irinotecan, and for patients who terminated HAI due to complications of the catheter system and gastroduodenal ulcer formation probably related to misdistribution of 5-FU, we administered either protracted venous infusion of 5-FU or MTX and 5-FU. Eleven patients were treated with irinotecan, three patients received protracted venous infusion of 5-FU and three patients MTX and 5-FU. The three treatment schedules were as follows:
(1) irinotecan 100 mg/m2 given as a 90 min intravenous infusion weekly or irinotecan 150 mg/m2 given as a 90 min intravenous infusion once every 2 weeks;
(2) 5-FU given as a protracted venous 24 h infusion at 250 mg/m2 per day;
(3) MTX 100 mg/m2 followed by 5-FU 600 mg/m2 3 h after MTX, each given every 2 weeks; all patients received leucovorin rescue, 10 mg/m2 orally every 6 h for six doses, 24 h after MTX injection.
Response and Toxicity Criteria
Response to measurable and evaluable sites of disease was assessed by computed tomography (CT) before the beginning of HAI and every 4 weeks during treatment. Response and toxicity were evaluated according to the World Health Organization guidelines (13).
Statistical Analysis
Overall survival was measured from the start of HAI to the date of death. The Kaplan–Meier method was used to estimate the overall survival curves (14). Survival time was censored at the close out date if the patients were alive.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
Twenty-six patients with liver metastases from colorectal cancer were entered in this study between October 1995 and October 1999 at the National Cancer Center Hospital. All 26 patients had either unresectable liver metastases or recurrent liver metastases after surgery for primary tumor or liver metastases. Patients’ characteristics before HAI are summarized in Table 1. Eleven patients had undergone previous surgery and 15 patients had unresectable liver metastases. They had no metastases other than liver metastases. None of them had received previous chemotherapy.
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Response and Duration of HAI
A summary of tumor response is shown in Table 2. An objective response was seen in 12 of 26 (46%; 95% confidence interval, 26.9–65.2%) patients, including two (8%) complete responses.
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The median number of treatment cycles given was 21 (range 7–75) and the median duration of treatment was 5.6 months. Discontinuation of the treatment was necessary in 23 patients. The reasons for termination are summarized in Table 3. Extrahepatic progression was observed in seven of 23 patients (30%). These included lung in four patients, lung and abdominal lymph node in one patient, abdominal lymph node in one patient and bone in one patient. Although 14 patients continued HAI until tumor progression occurred, other patients terminated HAI because of technical complications and clinical conditions. In four patients, the treatment was discontinued owing to complications related to the catheter system, hepatic artery thrombosis in three patients and arterial–portal shunt in one patient. Three patients stopped HAI because of gastroduodenal ulcer formation probably related to misdistribution of the drugs. In one patient who was a responder, hepatectomy was performed, and one patient refused to continue the treatment after 30 injections.
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Toxicity in HAI
The toxicity observed in this study is summarized in Table 4. No treatment-related death was observed. Hematological toxicity was minimal, with one patient developing grade 3 leukocytopenia and another patient grade 3 thrombocytopenia. Nausea and vomiting were the most common adverse reactions in nine of 26 patients (35%), followed by gastroduodenal ulcers in four patients (15%). Stomatitis, diarrhea and hand–foot syndrome were minor problems. No chemical hepatitis or sclerosing cholangitis were observed.
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Among four patients with gastroduodenal ulcers, one patient developed a severe complication, perforation of the duodenum and he was operated on. The other three patients recovered with only medical treatment.
Results of Second-line Systemic Chemotherapy
Results of the second-line systemic chemotherapy are shown in Table 5. No clinical response was observed in any of the 17 evaluable patients.
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Survival
With a 16.5-month median follow-up, the median survival time of all 26 patients after the first treatment was 19.4 months (Fig. 1).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Prospective, randomized studies of patients with unresectable liver metastases from colorectal cancer have shown significantly higher response rates for HAI than for systemic chemotherapy without impact on the overall survival. In Japan, HAI of 5-FU for liver metastases from colorectal cancer has been widely performed. It has been reported that weekly HAI of 5-FU has demonstrated a high response rate of 78% and a median survival duration of 25.8 months in 32 patients. Furthermore, it caused no serious toxicities and no decrease in the patients’ quality of life (12). The current study demonstrated a response rate of 46% (consisting of two complete responses and 12 partial responses among 26 cases) similar to most other randomized HAI studies (6–11). Although direct comparison of results from this study with the phase II study reported by Arai et al. (12) is difficult, given that the studies differ with respect to population characteristics, our study failed to reproduce the response rate to weekly HAI of 5-FU reported by Arai et al. One of the reasons for this might be complications associated with the HAI catheter system. Great care should be taken to prevent or quickly detect any disorders resulting from technical factors and if necessary, an adequate countermeasure should be taken as described by Arai et al.
No definite survival advantage due to the development of extrahepatic progression has been demonstrated. In this study, extrahepatic progression was observed in one-third of the patients with termination of HAI. Further attempts, such as a combination with systemic chemotherapy to prevent extrahepatic progression, are needed to prolong overall survival.
There have been few reports about the impact of second-line systemic chemotherapy in patients refractory to HAI. In the present study, the efficacy of second-line chemotherapy after termination of HAI was evaluated. Irinotecan is active in patients with advanced colorectal cancer as second-line therapy after failure of first-line 5-FU-based treatment (15). We reported previously that an MTX plus 5-FU regimen and protracted venous infusion of 5-FU produced relatively high response rates, 25% in both regimens, in pretreated patients with advanced colorectal cancer (16,17). However, in the present study, 17 cases with liver metastases or extrahepatic metastases failed to respond to second-line systemic chemotherapy including irinotecan. This might be due to prior exposure to the intensive treatment with high-dose 5-FU. The small number of patients, however, precludes any further conclusions as far as second-line chemotherapy is concerned.
In conclusion, this study showed an average response rate similar to those in most other randomized HAI studies and a median survival time of 19.4 months, which appears to be better than that of regional therapies reported previously. However, extrahepatic progression was observed in one-third of patients on termination of HAI and a response to second-line chemotherapy was not demonstrated. Regional treatment with systemic chemotherapy should be conducted to achieve good results in terms of survival. To this end, the Japan Clinical Oncology Group (JCOG) is now preparing a phase I/II study of weekly HAI of 5-FU with concurrent systemic irinotecan in patients with liver metastases from colorectal cancer.
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FOOTNOTES |
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+ For reprints and all correspondence: Yasuhide Yamada, Gastrointestinal Oncology Division, National Cancer Center Hospital, 5–1–1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: yayamada{at}ncc.go.jp
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Received May 7, 2002; accepted November 26, 2002
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