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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 1  |  Page : 84-90

Randomized controlled Phase III study comparing hepatic arterial infusion with systemic chemotherapy after curative resection for liver metastasis of colorectal carcinoma: JFMC 29–0003


1 Department of Surgery, Kushiro Rosai Hospital, Kushiro, Japan
2 Department of Surgery, Southern TOHOKU General Hospital, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan
3 Department of Surgery, Keio University School of Medicine, Tokyo, Japan
4 Department of Surgery, Machida Keisen Hospital, Japan
5 Department of Medical Laboratory and Blood Center, Asahikawa Medical University, Asahikawa, Japan
6 Department of Surgery, Hijirigaoka Hospital, Date, Japan
7 Department of Gastrointestinal Surgery, Toho University, Tokyo, Japan
8 Department of Surgery, Totsuka Kyouritsu Daiichi Hospital, Yokohama, Japan
9 Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
10 Department of Surgery, Tokai Central Hospital, Kakamigahara, Japan
11 Translational Research and Clinical Trial Center, Hokkaido University Hospital, Sapporo, Japan
12 Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan

Date of Web Publication16-May-2017

Correspondence Address:
Michitaka Honda
Department of Surgery, Southern TOHOKU General Hospital, Southern TOHOKU Research Institute for Neuroscience, Koriyama, 7-115 Yatsuyamada, Koriyama, Fukushima 963-8563
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.184524

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 > Abstract 

Background: The feasibility and efficacy of adjuvant hepatic arterial infusion (HAI) in preventing the development of liver metastases in patients with advanced colon carcinoma have not been validated. The aim of this randomized controlled study was to compare the feasibility of HAI and the protective effect against liver metastasis after curative resection to those of systemic chemotherapy.
Methods: Between July 2000 and June 2003, 91 patients were enrolled. Patients were randomly assigned to receive 5-fluorouracil (5-FU) via continuous venous infusion (CVI) or intra-hepatic arterial weekly high-dose 5-FU (WHF). The primary endpoint was overall survival (OS).
Results: In the WHF group, the cumulative failure rate of hepatic arterial catheterization was 16.7% at 6 months. The occurrence of grade 3 adverse events was comparable between the groups. The 5-year OS rates were 59.0% in the CVI group and 34.9% in the WHF group (P = 0.164). CVI tended to show a protective effect against liver metastasis regarding the 5-year liver-specific cumulative recurrence rate: CVI, 45.0% vs. WHF, 68.3%; P = 0.037).
Conclusion: HAI therapy has a certain protective effect against liver metastasis after curative resection in patients with colorectal cancer. However, this therapy did not contribute to any marked improvement in their overall survival.

Keywords: Adjuvant chemotherapy, colorectal cancer, hepatic arterial infusion, liver metastasis, prognosis


How to cite this article:
Kusano M, Honda M, Okabayashi K, Akimaru K, Kino S, Tsuji Y, Watanabe M, Suzuki S, Yoshikawa T, Sakamoto J, Oba K, Saji S. Randomized controlled Phase III study comparing hepatic arterial infusion with systemic chemotherapy after curative resection for liver metastasis of colorectal carcinoma: JFMC 29–0003. J Can Res Ther 2017;13:84-90

How to cite this URL:
Kusano M, Honda M, Okabayashi K, Akimaru K, Kino S, Tsuji Y, Watanabe M, Suzuki S, Yoshikawa T, Sakamoto J, Oba K, Saji S. Randomized controlled Phase III study comparing hepatic arterial infusion with systemic chemotherapy after curative resection for liver metastasis of colorectal carcinoma: JFMC 29–0003. J Can Res Ther [serial online] 2017 [cited 2019 Dec 15];13:84-90. Available from: http://www.cancerjournal.net/text.asp?2017/13/1/84/184524


 > Introduction Top


The liver is one of the most common sites of metastasis from colorectal cancer. In fact, 15% of patients with colorectal cancer have liver metastases at the time of the initial diagnosis, and 83% of the patients with metastatic diseases have liver metastases.[1] The 5-year survival rate is reported to range from 30% to 50% after complete tumor resection,[2],[3] whereas up to 70% of these patients experience disease recurrence.[4] Nearly, half of the recurrences after curative liver resection involve the liver, with recurrence being restricted to the liver in the vast majority of cases.

Hayashi et al. observed the presence of circulating colorectal cancer cells within the portal vein during surgery, suggesting that micrometastases might have already existed before surgery in patients who developed liver metastases after surgery.[5] Angiographic findings revealed that liver metastases from colorectal cancer receive abundant blood supply from the branches of hepatic arteries.[6],[7],[8] These facts are helpful for understanding the importance of liver-specific treatment to decrease the mortality and risk of recurrent disease attributable to colorectal cancer. Based on this theoretical background, the first randomized controlled study addressing the effect of portal vein infusion (PVI) of 5-fluorouracil (5-FU) on liver metastasis was conducted in 1979.[9] Compared to the control group, the perioperative PVI group exhibited a prominent decrease in mortality rate (11% [7/64] vs. 33% [23/69]) and a low-liver metastasis rate (1.6% [1/64] vs. 7.2% [5/69]). Subsequently, several clinical trials demonstrated that hepatic arterial infusion (HAI) of 5-FU or 5-fluorodeoxyuridine (FUDR) resulted in a significantly better progression-free survival compared to systemic chemotherapy in patients with colon carcinoma with liver metastasis.[10],[11],[12] Only a few studies were conducted to assess the effects of prophylactic HAI chemotherapy on the development of liver metastases, and on survival in patients with advanced colon carcinoma without apparent liver metastases.[13],[14]

Despite its effect on liver metastasis from colorectal cancer, complications related to HAI, i.e., hepatic artery thrombosis, catheter displacement, hematomas, infections, and inappropriate liver perfusion, have been reported.[15] These complications often require discontinuation of HAI, which might consequently result in a decreased survival rate. These complications were strongly associated with the skill of each operator, which might be one of the potential cofounders related to postoperative survival outcomes. These potential risks are associated with a lack of evidence of the effectiveness of HAI, and consequently, the feasibility and efficacy of HAI have not been fully validated to date.

The aim of this randomized controlled study was to compare the feasibility of HAI and its protective effect against disease recurrence after curative liver resection to those of systemic adjuvant chemotherapy. In addition, this study also assessed patient-reported outcomes during the administration of chemotherapy.


 > Methods Top


Eligibility criteria

This trial was approved by the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) and the institutional review boards of each participating institution. The study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Signed written informed consent was obtained from all patients before registration and randomization. The eligibility criteria were as follows: (1) curative resection for primary colorectal cancer and histologically proven synchronous or metachronous liver metastasis, (2) absence of other metastatic lesions, (3) no previous treatment for liver metastases, such as liver resection, chemotherapy, or radiotherapy, (4) age between 20 and 75 years, (5) Eastern Cooperative Oncology Group performance status of 0–2, (6) well preserved other organ function, and (7) negative tumor resection margins. Eligible patients were randomly assigned to receive 5-FU via continuous venous infusion (CVI) or intra-arterial weekly high-dose 5-FU (WHF). Randomization was performed centrally by the JFMC data center, and patients were stratified by the presence of colon or rectal cancer, Dukes classification of A, B, C, or D, synchronous or metachronous liver metastasis, and the number of liver metastases (1 or > 1).

Treatments

Continuous venous infusion group

The planned chemotherapy treatment was started after recovery from surgery. 5-FU was continuously administered at a dose of 300 mg/m 2/day for 5 days a week. If possible, the treatment was continued for at least 4 months. After 4 months, the decision to stop or continues the treatment was made in consultation with the patient.

Weekly high-dose 5-FU group

In patients assigned to the WHF group, a catheter was inserted and placed at an appropriate point by an experienced radiologist. The chemotherapeutic agent was administered via the catheter placed within the common hepatic artery. Malperfusion was corrected through angiographic embolization of aberrant vessels. An intra-arterial pump was connected to the implanted reservoir with a percutaneous needle. Intra-arterial 5-FU was continuously administered at a dose of 1000 mg/m 2 for 24 h and every week. If possible, the treatment was continued for at least 6 months. After 6 months, the decision to stop or continue treatment was made after consulting with the patient. Computed tomography (CT) angiography or digital subtraction angiography was performed at 3 and 6 months to confirm intrahepatic drug permeability in individual institutions. If necessary, the position of the catheter was modified for optimum function.

Endpoints

The primary endpoint was overall survival (OS), and the secondary endpoints were recurrence-free survival (RFS), the hepatic recurrence rate, and the extrahepatic recurrence rate. Survival was defined as the time from randomization to death due to any cause. The data of patients who were lost to follow-up were censored for these endpoints at the date of the last contact. RFS was defined as the time from randomization to documentation of disease recurrence (either hepatic or extrahepatic) or death due to any cause.

Follow-up examinations and assessment of health-related quality of life

Once chemotherapy was initiated, a complete blood count and biochemical analyses (total protein, serum albumin, aspartate aminotransferase or alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, choline esterase, direct and total bilirubin, and serum creatinine measurements) were performed every week during adjuvant chemotherapy. Tumor markers (carcinoembryonic antigen and carbohydrate antigen 19-9) were measured every month. These blood tests were repeated every 3 months after the completion of protocol-directed treatment. CT or ultrasonography was performed every 3 months after the completion of protocol-directed treatment. Colonoscopy was performed annually. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 1.0. Health-related quality of life (QoL) was assessed according to the 26-question modified QoL questionnaire for patients with cancer who are treated with anticancer drugs.[16] The questionnaires were administered at baseline and 2, 3, and 6 months after registration.

Statistical analysis

The sample size calculation (300 patients) was based on the primary endpoint. We assumed that the 5-year survival rate would be 30% in the CVI group and 50% in the WHF group (two-sided α = 0.05; β = 0.1). We assumed a duration of 2 years for enrollment and 5 years for follow-up; thus, the required sample size was 140 patients for each group. To account for participant dropout, the number of patients to be accrued was set at 300 in total.

Frequency tables using the Chi-square test or the Fisher exact test were used to explore the relationships between dichotomous variables. The distributions of time to recurrence, RFS, and OS were estimated using the Kaplan–Meier method. Cox proportional hazards models were used to explore the associations of covariates with time to recurrence, disease-free survival, and OS. All reported P values are two-sided unless otherwise specified. SAS version 9.1.3 (SAS Institute Inc., Cary, NC, USA) and R version 2.7.2 (R Project for Statistical Computing; http://www.r-project.org) were used for statistical analyses.


 > Results Top


Patient characteristics

A Consolidated Standards of Reporting Trials diagram showing the flow of participants in each stage of the current study is presented in [Figure 1]. Between July 2000 and June 2003, 91 patients were enrolled in this study. Of these, 46 were randomly assigned to the CVI group, and 45 were assigned to the WHF group. As 1 patient assigned to the CVI group refused to receive additional chemotherapy before starting the first protocol treatment, 90 patients (CVI group, 46 patients; WHF group, 44 patients) met our eligibility criteria and constituted the full analysis set population for this analysis. No significant difference in patient characteristics was noted between the CVI and WHF groups [Table 1].
Figure 1: The flowchart for this study as per the “Consolidated Standards of Reporting Trials” guidelines

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Table 1: Baseline characteristics of patients in the continuous vein infusion and weekly high-dose 5-fluorouracil groups

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Compliance with chemotherapy and adverse effects

The data regarding compliance with chemotherapy and adverse events were available for 42 patients in the CVI group and for 37 patients in the WHF group [Table 2]. Of these, the protocol-specified treatment was discontinued in 3 (7.1%) and 7 (18.9%) patients in the CVI and WHF groups, respectively, whereas dose reductions were necessary in 4 (4.1%) and 9 (24.3%) patients in the CVI and WHF groups, respectively. The differences observed in the rates of treatment discontinuation and dose reduction between the CVI, and WHF groups were not statistically significant. However, a significant difference was observed in the compliance index between the CVI and WHF groups (P = 0.002), suggesting a difference in the dose intensities between the treatment protocols. In the WHF group, the cumulative failure rates of hepatic arterial catheterization were 14.8% at 3 months and 16.7% at 6 months. Treatment delays and dose reductions were observed frequently with HAI (treatment delays: CVI, 7.1% vs. WHF, 18.9%; dose reduction: CVI, 9.5% vs. WHF, 24.3%). The incidences of adverse events were comparable between the CVI and WHF groups [Table 3]. Although the incidences of nausea, diarrhea, and general fatigue were significantly higher in the WHF group, the Grade 3 adverse events were identified as gastrointestinal toxicities such as appetite loss (WHF, 1 case), vomiting (WHF, 1 case), and diarrhea (CVI, 1 case; WHF, 2 cases). However, there was no significant difference in the adverse event rates between the two groups, indicating that no specific adverse effect was related with the insertion of the arterial catheter in this study.
Table 2: Compliance with chemotherapy

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Table 3: Acute adverse events

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Survival and RFS

The mean follow-up period was 6 years. Postoperative tumor recurrence or death was identified in 58 patients, 24 patients in the CVI group, and 34 patients in the WHF group. Of these, 17 patients in the CVI group and 24 patients in the WHF group developed liver metastasis. The 5-year OS rates were 59.0% in the CVI group and 34.9% in the WHF group (log-rank test, P = 0.146; [Figure 2]a). The hazard ratio of WHF compared to CVI for OS was 1.55 (95% confidence interval [CI] = 0.86–2.81, P = 0.150). In contrast, the 5-year RFS rates were significantly different between the groups (CVI, 44.1% vs. WHF, 20.4%; log-rank test, P = 0.038; [Figure 2]b). To evaluate whether WHF has a liver-specific protective effect, the cumulative incidence of recurrence was assessed separately from hepatic and extrahepatic recurrence. Interestingly, CVI had a protective effect against liver metastasis (5-year liver-specific RFS rate: CVI, 45.0% vs. WHF, 68.3%; log-rank test, P = 0.037; [Figure 2]c). The hazard ratio for liver-specific RFS was 1.92 (95% CI = 1.03–3.58, P = 0.040).
Figure 2: Kaplan–Meier curves for the weekly high-dose 5-FU and continuous venous infusion groups. (a) Overall survival curve. There was no significant difference between the two groups (log-rank test, P = 0.146). (b) Recurrence-free survival (RFS) curve. The continuous venous infusion group had a significantly better RFS rate (log-rank test, P = 0.038). (c) Liver-specific RFS curve. Continuous venous infusion tended to show a protective effect against liver metastasis (log-rank P = 0.077). CVI = Continuous vein infusion, WHF = Weekly high-dose 5-fluorouracil

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Quality of life

Sixty-two patients (CVI, 34 patients; WHF, 28 patients) completed the entire study (i.e., completed all QoL assessments, those at baseline, and 2, 3, and 6 months). The most common reason for patient dropout was patient refusal because of tumor recurrence and deterioration in clinical status. Patients enrolled in the WHF group had worse physical condition scores than those in the CVI group. No difference between the groups was found for daily activity, psychological condition, and social attitude.


 > Discussion Top


The results of this study clearly suggest that adjuvant HAI after liver resection did not improve OS and RFS compared to systemic chemotherapy. These results may be attributable to the lower completion rate of planned treatment with HAI. In addition, HAI had no protective effect against adverse events during adjuvant chemotherapy and no beneficial effect on QoL. These results have a number of important implications for future clinical practice and research. These data suggest that adjuvant chemotherapy after liver resection should be administered intravenously.

Several randomized controlled studies have demonstrated that adjuvant HAI after hepatic resection inhibits recurrence in the residual liver and improves disease-free survival, contrary to the findings of this study.[13],[14],[17] Kemeny et al. demonstrated that HAI with FUDR plus systemic therapy (5-FU/leucovorin) was associated with a superior 2-year survival rate of 86% versus 72% for systemic therapy alone (P = 0.03).[14] The same study group recently reported the outcomes of patients who received HAI with FUDR plus systemic chemotherapy with oxaliplatin, 5-FU, and LV after hepatic resection. In a Phase I study, the rate of recurrence in the residual liver was 11%, in addition to a 5-year hepatic RFS rate of 86%, and a 5-year disease-free survival rate of 50%.[18] In the NCCTG/NSABP study, systemic capecitabine and oxaliplatin alternating with HAI with FUDR were associated with a 2-year survival rate of 88% with no hepatic recurrence in 80% of the patients.[19] The inconsistency between these studies and this study can be explained by a difference in the hepatic extraction rate of FUDR compared to 5-FU. The hepatic extraction rate is 94–99% for FUDR compared to only 19–54% for 5-FU.[20] This metabolic disparity confounded the expectation of HAI in this study.

This study demonstrated that HAI was associated with promising intrahepatic drug distribution after 6 months, and insertion of the hepatic arterial catheter was feasible. Complications related with catheterization, including thrombosis of the hepatic artery, catheter displacement, and thrombotic catheter occlusion, are serious problems due to their direct association with treatment discontinuation, and these complications were observed in 4–56% of patients in previous research,[15] indicating that the results in this study were superior to those of previous studies regarding complications. Campbell et al. stated that these catheter-related complications were closely associated with the experience and skill of the operator.[21] A possible explanation for this finding is that catheter placement was performed by expert radiologists at individual institutions after a consensus meeting on anatomical and technical issues. However, it is notable that approximately 20% of patients developed catheter-related complications. Given the increasing acceptance of HAI, further research is needed to clarify the risk factors for catheter-related complications and common problems associated with catheter placement.

There are few reports on the QoL of patients receiving HAI. In the view of the pharmacokinetics, HAI should deliver high concentrations of drugs to liver metastases and enhance the half-lives of drugs, which are primarily metabolized in the liver. In general, it appears that HAI can allow extremely low drug concentrations to be maintained in the peripheral blood, thereby minimizing the risk of systemic adverse events and improving the QoL of patients.[22] Contrary to the theoretical expectations, this study did not identify a significant protective effect of HAI against systemic adverse effects. It is difficult to explain this discrepancy, but it might be related to 2 factors. First, the drug utilized in HAI was 5-FU that has a longer half-life than FUDR. Second, the dose of 5-FU might have been low in the CVI group, consequently underestimating the adverse effects caused by CVI. Considering the current increased need for patient-reported outcomes in cancer chemotherapy, this study provided important information for conducting future clinical research related to HAI.

The current study had some limitations. Only 91 patients were enrolled, which was below the planned sample size. Consequently, the statistical power of this study was not sufficient to provide conclusive results. Low patient accrual was mainly due to the invasiveness and technical difficulty of hepatic arterial catheter placement. Furthermore, because the study was conducted in 1999, the 5-FU monotherapy was applied as opposed to standard adjuvant chemotherapy for patients who underwent curative resection. However, the current standard regimen for patients with stage III colon cancer has been the combination therapy of oxaliplatin, 5-FU, and folinic acid (FOLFOX) or capecitabine plus oxaliplatin (XELOX).[23],[24],[25] Our regimen was probably less suitable than modern combination adjuvant chemotherapy. Although the findings from a recent comparative study suggested that combination therapy of HAI with oxaliplatin and systemic 5-FU administration might help improve the disease-free survival duration for patients with colorectal liver metastases after curative resection,[17] Kemeny et al. reported that the addition of bevacizumab to adjuvant HAI plus systemic therapy after liver resection did not improve RFS.[26] The results of the EORTC 40983 study indicate that perioperative systemic adjuvant chemotherapy after liver resection did not improve the rate of OS.[27] Further research will be needed to clarify the impact of HAI in patients who undergo resection of hepatic metastases from colorectal cancer.


 > Conclusion Top


The findings of this study suggested that WFH therapy might have a certain protective effect against liver-specific recurrence, and a significant difference was noted in the OS between patients who did and did not receive this therapy. Given the study limitations, further research will be required to confirm the efficacy of HAI using this modern regimen.

Acknowledgment

This study was supported by The Japanese Foundation for Multidisciplinary Treatment of Cancer and in part by the Epidemiological and Clinical Research Information Network (ECRIN), a nonprofit organization. We thank all the members of JFMC29-003: Satoru Todo, Hokkaido University Graduate School of Medicine; Koichi Hirata, Sapporo Medical University School of Medicine; Shinichi Kasai, Asahikawa Medical University; Yukifumi Kondo, JA Sapporo Kosei Hospital; Yoshio Katsuki, Nikko Memorial Hospital; Masahiro Takahashi, Asahikawa-Kosei General Hospital; Mutsuo Sasaki, Hirosaki University; Go Wakabayashi, Iwate Medical University; Michiaki Unno, Tohoku University School of Medicine; Mitsukazu Gotoh, Fukushima Medical University; Seiichi Takenoshita, Fukushima Medical University; Isamu Koyama, Saitama Medical University; Tatsuya Aoki, Tokyo Medical University; Shingo Kameoka, Tokyo Women's Medical University; Tetsuichiro Muto, Cancer Institute Hospital; Ikuo Nagashima, Teikyo University; Tadatoshi Takayama, Nihon University; Kazuyoshi Ishibashi, Showa University Fujigaoka Hospital; Hiroshi Shimada, Yokohama City University; Katsuyoshi Hatakeyama, Niigata University; Kazuhiro Tsukada, Toyama University; Tetsuo Ohta, Kanazawa University; Hiromi Tanemura, Gifu Municipal Hospital; Akihiro Yamaguchi, Ogaki Municipal Hospital; Yoshitaka Inaba, Aichi Cancer Center Hospital; Tadao Manabe, Nagoya City University; Toshiaki Nonami, Aichi Medical University; Masaki Kashiwazaki, National Hospital Organization Osaka National Hospital; Morito Monden, Osaka University; Shunichi Tsujitani, Tottori University; Noriaki Tanaka, Okayama University; Toshimasa Asahara, Hiroshima University; Hiroshima University, Tokushima University; Tadashi Horimi, Kochi Municipal Central Hospital; Hiroshi Ishikawa, Sasebo City General Hospital. We thank Shigetoyo Saji, Yoshitaka Furuta and Ms. Minako Nakashima for their assistance.

Financial support and sponsorship

The Japanese Foundation for Multidisciplinary Treatment of Cancer and in part by the Epidemiological and Clinical Research Information Network (ECRIN), a nonprofit organization.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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