Elsevier

European Journal of Cancer

Volume 50, Issue 13, September 2014, Pages 2231-2240
European Journal of Cancer

Clinical Trial
Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: Final results of JCOG0205

https://doi.org/10.1016/j.ejca.2014.05.025Get rights and content

Abstract

Background

NSABP C-06 demonstrated the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) with respect to disease-free survival (DFS) for stage II/III colon cancer. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofolinate (l-LV) for stage III colorectal cancer patients who have undergone Japanese D2/D3 lymph node dissection.

Methods

Patients were randomised to three courses of 5-FU/l-LV (5-FU 500 mg/m2, l-LV 250 mg/m2 on days 1, 8, 15, 22, 29, 36 every 8 weeks) or five courses of UFT/LV (UFT 300 mg m−2 day−1, LV 75 mg/day on days 1–28 every 5 weeks). The primary end-point was DFS. The sample size was 1100 determined with one-sided alpha of 0.05, power of 0.78 and non-inferiority margin of hazard ratio of 1.27. This trial is registered with UMIN-CTR (C000000193).

Findings

Between February 2003 and November 2006, 1,101 patients (1092 eligible patients) were randomised to 5-FU/l-LV (n = 550) or UFT/LV (n = 551). Median age: 61 years, colon/rectum: 67%/33%, number of positive nodes ⩽3/>3: 73%/27%, stage IIIa/IIIb: 75%/25%. The hazard ratio of DFS was 1.02 (91.3% confidence interval, 0.84–1.23), demonstrating the non-inferiority of UFT/LV (P = 0.0236). Five-year overall survival (87.5%) was higher than that in NSABP C-06 (69.6%). Grade 3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% alanine aminotransferase elevation in UFT/LV, respectively. The incidences of diarrhoea (9.6% versus 8.5%) and anorexia (4.0% versus 3.7%) were similar between the two arms. No treatment-related deaths were reported.

Interpretation

Adjuvant UFT/LV is non-inferior to standard 5-FU/l-LV with respect to DFS. UFT/LV should be an oral treatment option for patients with stage III colon cancer who have undergone Japanese D2/D3 lymph node dissection.

Introduction

The number of colorectal cancer patients has been increasing rapidly worldwide in recent decades. In Japan, the incidence of newly diagnosed colorectal cancer in 2007 was 109,140 cases (63,182 in men and 45,958 in women). In 2011, there were 45,744 deaths from colorectal cancer (24,862 men and 20,882 women) [1].

Postoperative adjuvant chemotherapy aims to reduce recurrence and improve overall survival (OS) in patients with stage III colorectal cancer. On the basis of the results of the MOSAIC, NSABP C-07 and XELOXA randomised trials, infusional fluorouracil and folinic acid with oxaliplatin (FOLFOX), and capecitabine and oxaliplatin (CapeOX) are widely used as standard postoperative adjuvant chemotherapy [2], [3], [4]. However, prolonged peripheral neuropathy, central venous access and cost of care are clinically significant problems with oxaliplatin-based adjuvant chemotherapy [5].

A combination of fluorouracil and levofolinate (5-FU/l-LV) was the standard adjuvant chemotherapy before the introduction of oxaliplatin-based combinations. Oral fluoropyrimidines have been commonly used as postoperative adjuvant chemotherapy in Japan for many years [6], [7]. Uracil and tegafur plus leucovorin (UFT/LV) previously demonstrated similar disease-free survival (DFS) and OS to 5-FU/LV in NSABP C-06 [8]. When our trial was initiated, oxaliplatin-based adjuvant chemotherapy was unavailable in Japan; therefore, we aimed to reconfirm the efficacy of oral adjuvant chemotherapy with UFT/LV compared to 5-FU/LV under the meticulous Japanese surgical procedure.

Historically, there have been several differences between the Japanese and Western surgical approaches to lymphadenectomy for cancers of various sites, particularly nomenclature and dissection extent [9]. In the seventh edition of the American Joint Committee on Cancer (AJCC) staging system [10], lymph node evaluation focuses on identifying the number of lymph nodes containing metastatic cancer. However, the Japanese Society for Cancer of the Colon and Rectum (JSCCR) classifies lymph node metastases on the basis of not only the number of positive lymph nodes, but also the location. Adequate lymphadenectomy including pericolic (D1 lymph-adenectomy), intermediate (D2) and additional main node dissection (D3) is indispensable for accurate staging and therapy. This approach is a standard procedure for Japanese colorectal surgeons, which was recently reported to result in better OS than in European countries [11], [12].

Accordingly, the primary objective of this randomised controlled trial was to confirm the non-inferiority of oral adjuvant chemotherapy UFT/LV to intravenous 5-FU/l-LV with respect to DFS. The secondary objective was to assess OS and adverse events in patients who underwent Japanese D2/D3 dissection and adjuvant chemotherapy without an oxaliplatin-based regimen.

Section snippets

Study design and participants

The inclusion criteria were histologically proven colorectal adenocarcinoma, mucinous carcinoma, signet ring-cell carcinoma; stage III colon cancer (caecum, ascending, transverse, descending or sigmoid) or upper rectal cancer (rectosigmoid, rectum above the peritoneal reflection), excluding patients with T2 or deeper synchronous multiple cancer; colectomy with D2 or D3 lymph node dissection; R0 resection; age 20–75 years; Eastern Clinical Oncology Group (ECOG) performance status 0 or 1; and no

Role of the funding source

The funding sources had no role in the design of the study; collection, analysis or interpretation of the data; writing of the report or in the decision to submit for publication. The corresponding author had full access to all the data in the study and final responsibility for the decision to submit the report for publication.

Results

The JCOG0205 is a prospective randomised, open-label, phase III trial in 47 centres in Japan. It was initiated in February 2003 and finished to accrual in November 2007 with 1101 patients including 550 and 551 in the 5-FU/l-LV and UFT/LV arms, respectively. Nine patients (0.8%, 4 and 5 assigned to the 5-FU/l-LV and UFT/LV arms, respectively) were ineligible. Fifteen patients did not receive chemotherapy. Seven out of nine ineligible patients received their assigned chemotherapy. According to

Discussion

JCOG0205 had a study design similar to that of NSABP C-06, aiming to confirm the non-inferiority of oral UFT/LV to intravenous 5-FU/l-LV with respect to DFS in stage III colon cancer. The present trial reconfirmed the non-inferiority of oral UFT/LV under the condition of D2/D3 lymph node dissection according to the Japanese guidelines.

UFT is a relatively old oral fluoropyrimidine that was developed in Japan in the 1980s. It has many indications for metastatic and advanced solid cancers

Systematic review

We searched PubMed and the abstracts of the American Society of Medical Oncology (ASCO) and ASCO Gastrointestinal Symposium, and European the Society of Medical Oncology (ESMO) from 1st January 2001 to 31st December 2012. We used MeSH and full-text search terms for colon cancer, adjuvant chemotherapy and randomised controlled trials. We selected articles in English published in the above mentioned period. We checked that the original articles described the results of the primary end-point, i.e.

Author contributions

Y.S., T.H. and Y.M. designed the trial, wrote the protocol and coordinated the study; Y.S., T.H., Y.M., N.S., Y.K., N.T., M.O., T.K., Y.T., T.S., N.T., S.Y., M.A., H.M., and Y.K. enrolled patients; J.M., K.N., and H.F. managed, analysed, and interpreted the data; Y.S. drafted the manuscript. All authors reviewed and revised the paper, and approved the submitted version.

Participating hospitals

National Cancer Center Hospital, National Cancer Center Hospital East, Aichi Cancer Center Hospital, Chiba Cancer Center, Osaka Medical Center for Cancer and Cardiovascular Diseases, Yamagata Prefectural Central Hospital, Niigata Cancer Center Hospital, Minoh Municipal Hospital, Kanagawa Cancer Center, Shizuoka Cancer Center, Kansai Rosai Hospital, National Hospital Organization Osaka National Hospital, National Hospital Organization Shikoku Cancer Center, National Defense Medical College,

Conflict of interest statement

Oral folinic acid tablets were provided by Nippon Wyeth-Ledery Pharmaceutical Co., Ltd. without compensation until September 2003 when the tablets were approved and commercially available in Japan.

Y.S. has received grants and personal fees from Taiho, Chugai, Yakult, and Pfizer; grants from Sanofi, Novartis and Eli Lilly; personal fees from Bayer, Bristol-Myers and Merk Serono. T.H. has received grants and personal fees from Taiho, Pfizer and Yakult; personal fees from Kyowa Kirin. J.M. have no

Acknowledgements

We sincerely appreciate the participation of the patients and their families. The authors are also grateful to Dr. Hiroshi Katayama for his assistance with writing the manuscript as well as Ms. Ayaka Nakano and Ms. Harumi Kaba for data management.

The study was supported in part by the National Cancer Center Research and Development Funds (23-A-16 and 23-A-19), Grants-in-Aid for Clinical Cancer Research (11S-4, 14S-3, 14S-4, 17S-3, 17S-5, 20S-3, and 20S-5), and Health Sciences Research Grants

References (19)

  • Cancer statistics in Japan. Available at: <http://ganjoho.jp/professional/statistics/backnumber/2012_jp.html>; 2012...
  • T. André et al.

    Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer

    N Engl J Med

    (2004)
  • G. Yothers et al.

    Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses

    J Clin Oncol

    (2011)
  • D.G. Haller et al.

    Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer

    J Clin Oncol

    (2011)
  • T. André et al.

    Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial

    J Clin Oncol

    (2009)
  • J. Sakamoto et al.

    An individual patient data meta-analysis of adjuvant therapy with uracil–tegafur (UFT) in patients with curatively resected rectal cancer

    Br J Cancer

    (2007)
  • T. Hamaguchi et al.

    Final results of randomized trials by the National Surgical Adjuvant Study of Colorectal Cancer (NSAS-CC)

    Cancer Chemother Pharmacol

    (2011)
  • B.C. Lembersky et al.

    Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06

    J Clin Oncol

    (2006)
  • Japanese Society for Cancer of the Colon and Rectum

    Japanese classification of colorectal carcinoma

    (2009)
There are more references available in the full text version of this article.

Cited by (104)

  • Adjuvant chemotherapy can prolong recurrence-free survival but did not influence the type of recurrence or subsequent treatment in patients with colorectal liver metastases

    2021, Surgery (United States)
    Citation Excerpt :

    Although liver resection is the only potentially curative treatment for resectable colorectal liver metastases (CRLM), half of all patients develop recurrences after liver resection.1,2 Uracil-tegafur and leucovorin (UFT/LV) has been used as a standard adjuvant regimen for colon cancer with lymph node metastasis.3,4 We conducted a randomized, controlled, phase 3 trial to test the hypothesis that the UFT/LV regimen might be useful for preventing recurrence after the resection of CRLM, compared with surgery alone.

View all citing articles on Scopus

Funding: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

View full text