Japanese Journal of Clinical Oncology Advance Access originally published online on April 23, 2009
Japanese Journal of Clinical Oncology 2009 39(6):406-409; doi:10.1093/jjco/hyp035
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© The Author (2009). Published by Oxford University Press. All rights reserved
A Randomized Phase II/III Trial Comparing Hepatectomy Followed by mFOLFOX6 with Hepatectomy Alone as Treatment for Liver Metastasis from Colorectal Cancer: Japan Clinical Oncology Group Study JCOG0603
1 Department of Gastroenterological Surgery, Aichi Cancer Center Hospital
2 Department of Surgery, Kamiiida Daiichi General Hospital
3 Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya
4 Department of Gastrointestinal Oncology Division, National Cancer Center Hospital
5 JCOG Data Center, Center for Cancer Control and Information Services, National Cancer Center, Tokyo
6 Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba
7 Colorectal Surgery Division, National Cancer Center Hospital, Tokyo, Japan
For reprints and all correspondence: Yukihide Kanemitsu, Department of Gastroenterological Surgery, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. E-mail: ykanemit{at}aichi-cc.jp
Received October 22, 2008; accepted March 15, 2009
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Abstract |
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 TOP Abstract INTRODUCTIONSTUDY PROTOCOLFundingConflict of interest statementReferences |
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A randomized controlled trial is being conducted in Japan to compare hepatectomy alone with hepatectomy followed by adjuvant chemotherapy as treatment in patients with curatively resected liver metastases from colorectal cancer to improve survival with intensive chemotherapy. Between 42 and 70 days after liver resection, patients are randomly assigned to either hepatectomy alone or hepatectomy followed by 12 cycles of modified FOLFOX6 (mFOLFOX6) regimen. A total of 300 patients (including 78 patients in Phase II) will be accrued from 38 institutions within 3 years. The primary endpoint is treatment compliance at nine courses of mFOLFOX6 regimen in Phase II and disease-free survival in Phase III. The secondary endpoints are overall survival, incidence of adverse events and patterns of recurrence.
Key Words: colorectal cancer • liver metastases • randomized controlled trial • mFOLFOX6
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSTUDY PROTOCOLFundingConflict of interest statementReferences |
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Approximately one-third of patients survive for 5 years following curative resection of hepatic metastases from colorectal cancer (1,2), and the proportion of hepatectomy-related death is as low as 1–2% (3–5). These observations strongly support the view that hepatectomy seems to be the most effective therapy for treating hepatic metastases from colorectal cancer, due to the potential for long-term survival that is not possible with other treatment modalities. However, a hepatectomy alone does not always provide a complete cure. Most recurrences occur in liver, lung or both within the first 2 years after hepatectomy. Adjuvant chemotherapy may reduce the risk of recurrence and improve long-term survival, but administering systemic agents to the patients with resectable hepatic metastases in the clinical practice is not universal. In their EORTC40983 trial, Nordlinger et al. (6) identified a prominent need for a well-conducted randomized trial to compare hepatectomy alone with combined hepatectomy and chemotherapy treatment in patients with resectable colorectal liver metastases. However, we question the strategy to give pre-operative chemotherapy to patients with resectable colorectal liver metastases, as this postponed a possible curative treatment. Patients who receive pre-operative chemotherapy often have a higher risk toward post-operative complications. Theoretically, post-operative chemotherapy should be effective toward microscopic residual disease in the remnant liver or body. Until the report of the AURC 9002 trial by Portier et al. (7), there was no clear evidence from a randomized trial demonstrating that post-operative chemotherapy, either systemic or by hepatic arterial infusion, was more beneficial than hepatectomy alone. In the 10 years needed to complete accrual for this trial, however, the original question became outdated due to the availability of more effective chemotherapy regimens containing potentially more active agents such as oxaliplatin, irinotecan, bevacizumab or cetuximab. It is therefore still unclear whether combined treatment with post-operative chemotherapy is better than hepatectomy alone in patients with resectable liver metastases from colorectal cancer.
The rationale for choosing FOLFOX regimen as the treatment arm in this trial is based on the results of the previous studies for Stage III patients and unresectable Stage IV patients. Oxaliplatin-based therapy is also a standard first-line treatment for advanced or metastatic unresectable colorectal cancer. We chose the modified FOLFOX6 (mFOLFOX6) regimen for the study, since it is the most convenient of the FOLFOX regimens and can be administered on an outpatient basis. In Japan, however, oxaliplatin was approved in April 2005, and we set a Phase II part in this trial to confirm the feasibility of mFOLFOX6 regimen in the Japanese population with resected liver metastases from colorectal cancer.
Accordingly, we have started a Phase II/III randomized controlled trial to evaluate mFOLFOX6 as post-operative chemotherapy for patients with curatively resected liver metastases from colorectal cancer.
The study protocol was designed by the Colorectal Cancer Study Group (CCSG) of the Japan Clinical Oncology Group (JCOG) and was approved by the Protocol Review Committee of JCOG on 15 February 2007. This trial was registered at the UMIN Clinical Trials Registry as UMIN000000653 (http://www.umin.ac.jp/ctr/index.htm) and was activated on 16 April 2007.
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Purpose
The aim of this study is to demonstrate the feasibility (Phase II) and the superiority of disease-free survival (Phase III) of systemic intravenous post-operative chemotherapy with mFOLFOX6 compared with hepatectomy alone in patients with curatively resected liver metastases from colorectal cancer.
Study Setting
The study was a multi-institutional prospective randomized Phase II/III trial, where participating institutions include 38 specialized centers as on 4 September 2008.
Resources
The study was supported by Health and Labour Sciences Research Grants for Clinical Cancer Research (h16-032 and h19-024) and Grants-in-Aid for Cancer Research (17S-3, 17S-5, 20S-3 and 20S-6), from the Ministry of Health, Labour and Welfare, Japan.
Endpoints
The primary endpoint in the Phase II part is treatment compliance at nine courses after beginning mFOLFOX6 [bolus and infusion fluorouracil (FU) and leucovorin (LV) with oxaliplatin] in all eligible patients. Treatment compliance at nine courses is defined as the proportion of patients in whom oxaliplatin is administered nine courses or more according to the protocol. The primary endpoint in the Phase III part is disease-free survival which is defined as days from randomization to first evidence of recurrence, secondary cancer or death from any cause, and it was censored at the latest day when the patient was alive without any evidence of recurrence or secondary cancer.
Secondary endpoints are overall survival, incidence of adverse events defined by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and patterns of recurrence after liver resection.
Eligibility Criteria
Primary tumors are staged according to the sixth edition of the tumor-nodes-metastasis classification system of the Union Internationale Contre le Cancer (UICC).
Inclusion Criteria
Prior to enrollment in the study, patients must fulfill all of the following criteria: the resected liver specimen consists of histologically proven adenocarcinoma of the colorectum. Potentially curative R0 resection was performed for both primary tumor and liver metastasis. In metachronous cases, the liver metastasis should be the first and the only recurrence. No extrahepatic metastasis or recurrence on chest and abdominal CT or MRI within 4 weeks before enrollment. No prior chemotherapy with oxaliplatin. No other chemotherapy or radiotherapy within 3 months before enrollment. No prior radiofrequency ablation or cryotherapy for liver metastasis. Time since their hepatectomy is between 42 and 70 days. Age is between 20 and 75 years old. European Cooperative Oncology Group (ECOG) performance status is 0–1. There are sufficient organ functions. Completed written informed consent from patient is obtained.
Exclusion Criteria
Patients are excluded if they meet any of the following criteria: (i) synchronous or metachronous multiple cancer, (ii) women during pregnancy or breast-feeding, (iii) psychosis, (iv) systemic steroids medication, (v) continuous use of flucytosine, phenytoin or warfarin potassium, (vi) insulin-dependent or poorly controlled diabetes mellitus and (vii) diarrhea or peripheral neuropathy greater than Grade 1.
Randomization
After the confirmation of the inclusion and exclusion criteria by telephone or fax to the JCOG Data Center, the patients are randomized to either hepatectomy alone arm or post-operative chemotherapy arm. The minimization method is used for randomization balancing the arms according to the state of liver metastases (synchronous/metachronous), the number of liver metastases (three or less/four or more), the largest size of liver metastases (<5/
5 cm) and the number of metastatic lymph nodes in the primary lesion (three or less/four or more/unknown), and institution.
Treatment Methods
In hepatectomy alone arm, the patients are observed without any treatment until recurrence. In post-operative chemotherapy arm, the treatment schedule is summarized in Fig. 1. Chemotherapy with mFOLFOX6 is initiated between 56 and 84 days following liver surgery. Chemotherapy consists of an intravenous injection of oxaliplatin 85 mg/m2 with L-LV 200 mg/m2 over 2 h followed by 5-FU 400 mg/m2 bolus and 2400 mg/m2 continuous infusion over 48 h. This cycle is repeated every 2 weeks for 12 courses until disease progression or unacceptable toxicity.
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Follow-up
Patient follow-up will be performed every 2 months for the first year, then every 4 months until the third year and every 6 months until the fifth year. Follow-up includes a clinical examination, analysis of tumor marker levels and thoracoabdominal computed tomography. Physicians will decide whether or not to treat recurrences, including administration of second-line chemotherapy.
Study Design and Statistical Method
The Phase II part of this trial is designed to evaluate the feasibility of the post-operative chemotherapy with mFOLFOX6. If the treatment compliance at nine courses of post-operative chemotherapy arm is high as expected in the Phase II part, the registration is continued for the Phase III part. In the Phase II part, the sample size was 78 cases, with 39 cases per arm, provided 90% power under the hypothesis of treatment compliance at nine courses as the expected value of 70% and the threshold value of 50% using one-sided testing at a 10% significance level. Randomization is also performed in the Phase II part, but any tests to compare two arms directly in terms of efficacy endpoints are not planned in the Phase II part.
The Phase III part of this trial is designed to confirm the superiority in terms of disease-free survival of hepatectomy followed by mFOLFOX6 to hepatectomy alone. The hypothesis of the Phase III part is the 5-year disease-free survival of post-operative chemotherapy arm is greater than that (25%) obtained by hepatectomy alone arm by 12%. If a statistically significant improvement in 5-year disease-free survival is demonstrated, post-operative chemotherapy followed by hepatectomy will be the new standard treatment. According to that, the planned sample size in the Phase III part including the cases registered in the Phase II part is 300 cases, 150 cases per arm, and 233 events are expected with 3 years of accrual and 5 years of follow-up.
This ensures at least 80% power with a one-sided 
of 5%.
Interim Analysis and Monitoring
An interim analysis is not planned in the Phase II part, and three interim analyses are planned in the Phase III part: the first at the time two-thirds of the total patients are registered, the second just after the completion of registration and the third at the time of 3-year follow-up. The Data and Safety Monitoring Committee (DSMC) of the JCOG will independently review the interim analysis reports and consider whether it is necessary to stop the trial prematurely. In-house interim monitoring will be performed by the Data Center to evaluate and improve the study progress and quality. Monitoring reports will be submitted to and reviewed by the DSMC and the CCSG every 6 months.
Participating Institutions (from North to South)
Sapporo-Kosei General Hospital, Miyagi Cancer Center, Yamagata Prefectural Central Hospital, Ibaraki Prefectural Central Hospital, Tochigi Cancer Center, Gunma Prefectural Cancer Center, Saitama Cancer Center, National Cancer Center Hospital East, Chiba Cancer Center, National Cancer Center Hospital, Keio University Hospital, Tokyo Medical and Dental Hospital, Kitasato University East Hospital, Kanagawa Cancer Center, Kitasato University Hospital, Showa University Northern Yokohama Hospital, Yokohama City University Medical Center, Niigata Cancer Center Hospital, Ishikawa Prefectural Central Hospital, Nagano Municipal Hospital, Shizuoka Cancer Center, Aichi Cancer Center Hospital, Fujita Health University Hospital, Kyoto Medical Center, Osaka University Hospital, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka National Hospital, Sakai Municipal Hospital, Minoh City Hospital, Suita Municipal Hospital, Kansai Rousai Hospital, Hyogo College of Medicine Hospital, Okayama Saiseikai General Hospital, Hiroshima University Hospital, Hiroshima City Hospital, Shikoku Cancer Center, Kurume University Hospital and Oita University Hospital.
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Funding |
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Ministry of Health, Labour and Welfare, Japan.
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Conflict of interest statement |
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None declared.
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References |
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6 Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet (2008) 37:1007–16.
7 Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol (2001) 24:4976–82.[CrossRef]
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