Elsevier

The Lancet

Volume 388, Issue 10041, 16–22 July 2016, Pages 248-257
The Lancet

Articles
Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01)

https://doi.org/10.1016/S0140-6736(16)30583-9Get rights and content

Summary

Background

Although adjuvant chemotherapy with gemcitabine is standard care for resected pancreatic cancer, S-1 has shown non-inferiority to gemcitabine for advanced disease. We aimed to investigate the non-inferiority of S-1 to gemcitabine as adjuvant chemotherapy for pancreatic cancer in terms of overall survival.

Methods

We did a randomised, open-label, multicentre, non-inferiority phase 3 trial undertaken at 33 hospitals in Japan. Patients who had histologically proven invasive ductal carcinoma of the pancreas, pathologically documented stage I–III, and no local residual or microscopic residual tumour, and were aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive gemcitabine (1000 mg/m2, intravenously administered on days 1, 8, and 15, every 4 weeks [one cycle], for up to six cycles) or S-1 (40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles) at the data centre by a modified minimisation method, balancing residual tumour status, nodal status, and institutions. The primary outcome was overall survival in the two treatment groups, assessed in the per-protocol population, excluding ineligible patients and those not receiving the allocated treatment. The protocol prespecified that the superiority of S-1 with respect to overall survival was also to be assessed in the per-protocol population by a log-rank test, if the non-inferiority of S-1 was verified. We estimated overall and relapse-free survival using the Kaplan-Meier methods, and assessed non-inferiority of S-1 to gemcitabine using the Cox proportional hazard model. The expected hazard ratio (HR) for mortality was 0·87 with a non-inferiority margin of 1·25 (power 80%; one-sided type I error 2·5%). This trial is registered at UMIN CTR (UMIN000000655).

Findings

385 patients were randomly assigned to treatment between April 11, 2007, and June 29, 2010 (193 to the gemcitabine group and 192 to the S-1 group). Of these, three were exlcuded because of ineligibility and five did not receive chemotherapy. The per-protocol population therefore consisted of 190 patients in the gemcitabine group and 187 patients in the S-1 group. On Sept 15, 2012, following the recommendation from the independent data and safety monitoring committee, this study was discontinued because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been finished. Analysis with the follow-up data on Jan 15, 2016, showed HR of mortality was 0·57 (95% CI 0·44–0·72, pnon-inferiority<0·0001, p<0·0001 for superiority), associated with 5-year overall survival of 24·4% (18·6–30·8) in the gemcitabine group and 44·1% (36·9–51·1) in the S-1 group. Grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase were observed more frequently in the gemcitabine group, whereas stomatitis and diarrhoea were more frequently experienced in the S-1 group.

Interpretation

Adjuvant chemotherapy with S-1 can be a new standard care for resected pancreatic cancer in Japanese patients. These results should be assessed in non-Asian patients.

Funding

Pharma Valley Center, Shizuoka Industrial Foundation, Taiho Pharmaceutical.

Introduction

Of the the phase 3 trials in this century of adjuvant treatment for pancreatic cancer, a few trials1, 2 have shown that postoperative adjuvant chemotherapy improves survival of patients with resected pancreatic cancer. In 2004, the European Study Group for Pancreatic Cancer 1 (ESPAC-1) trial1 showed that adjuvant chemotherapy (fluorouracil plus folinic acid) had a significant survival benefit in patients with resected pancreatic cancer, whereas no additional effect of radiation therapy was observed. In 2007, the Charité Onkologie (CONKO)-001 trial2 showed that adjuvant chemotherapy with gemcitabine not only delayed recurrence, but also improved survival compared with surgery alone. However, no further substantial progress has been made since then, and the survival of patients with pancreatic cancer after macroscopically curative resection still remains low (5-year survival of 20·7–23·9%, median survival of 22·3–23·6 months) even after use of adjuvant chemotherapy.3, 4, 5

Research in context

Evidence before this study

We searched PubMed for phase 3 trials of adjuvant treatment for pancreatic cancer published between Jan 1, 2000, and Dec 31, 2015. We searched using the terms “pancreatic cancer”, “adjuvant chemotherapy” with the limitation by “clinical trial phase 3” and “published between 2000 and 2015”, excluding “neoadjuvant” and “locally advanced”. A few trials have shown that postoperative adjuvant chemotherapy improves survival of patients with resected pancreatic cancer. However, survival of patients with pancreatic cancer after macroscopically curative resection still remains low.

Added value of this study

Postoperative adjuvant chemotherapy with S-1 significantly increased both overall and relapse-free survival of Japanese patients with resected pancreatic cancer compared with gemcitabine. S-1 was well tolerated in the adjuvant setting and has the potential to contribute to improve patients' quality of life.

Implications of all the available evidence

Adjuvant chemotherapy with S-1 can be a new standard care for resected pancreatic cancer in Japanese patients. These results should be assessed in non-Asian patients.

S-1 (TS-1; Taiho Pharmaceutical, Tokyo, Japan) is an oral drug containing tegafur (a prodrug of fluorouracil), gimeracil, and oteracil potassium (in a molar ratio of 1:0·4:1).6 S-1 is characterised by inhibition of dihydropyrimidine dehydrogenase (DPD) activity by gimeracil, maintaining high concentration of fluorouracil in blood and tumour tissue, and by suppression of phosphorylation of fluorouracil in the gastrointestinal tract by oteracil potassium, reducing gastrointestinal toxicity. S-1 monotherapy showed responses ranging from 21·1% to 37·5% in the phase 2 studies for metastatic pancreatic cancer.7, 8 Thereafter, S-1 showed a higher response and non-inferiority in terms of overall survival than did use of gemcitabine for patients with advanced pancreatic cancer.9 S-1 is recognised to be standard adjuvant chemotherapy for patients with resected gastric cancer in Japan, and is widely used in Asian countries because of its convenience of administration and good effectiveness.10 Moreover, S-1 has a different toxicity profile from gemcitabine, which is considered to have some positive effects on quality of life. Therefore, we expected an equivalent or higher survival benefit of S-1, compared with gemcitabine, in the adjuvant setting for resected pancreatic cancer. The aim of this trial was to verify the non-inferiority of S-1 to gemcitabine as adjuvant chemotherapy for resected pancreatic cancer in terms of overall survival, with respect to patient's quality of life.

Section snippets

Study design

We did a randomised, open-label, multicentre, non-inferiority phase 3 trial of adjuvant chemotherapy with S-1 versus gemcitabine in patients with curatively resected pancreatic cancer, the Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC) 01 trial.11 We completed this trial at 33 hospitals (13 university hospitals, ten cancer centre hospitals, ten general hospitals) in Japan (appendix). All medical procedures were covered by the Japanese national social insurance system.

The trial was

Results

Between April 11, 2007, and June 29, 2010, a total of 385 patients (median of six patients enrolled from each hospital, range 1–43) were enrolled; 193 patients were randomly assigned to the gemcitabine group and 192 to the S-1 group (figure 1). After randomisation, three patients were found to be ineligible. Five patients did not receive any adjuvant chemotherapy. As a result, 190 patients in the gemcitabine group and 187 in the S-1 group constituted the per-protocol population (figure 1).

Discussion

This randomised phase 3 trial clearly showed significantly improved overall survival of patients with resected pancreatic cancer with adjuvant S-1 chemotherapy compared with adjuvant gemcitabine, associated with higher 5-year survival in the S-1 group than in the gemcitabine group.

In this century, several notable trials have been completed including gemcitabine and other drugs, and gemcitabine monotherapy has been used worldwide as a standard treatment for resected pancreatic cancer. Oettle and

References (24)

  • R Brooks

    EuroQol: the current state of play

    Health Policy

    (1996)
  • JP Neoptolemos et al.

    A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer

    N Engl J Med

    (2004)
  • H Oettle et al.

    Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial

    JAMA

    (2007)
  • H Ueno et al.

    A randomized phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer

    Br J Cancer

    (2009)
  • JP Neoptolemos et al.

    Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial

    JAMA

    (2010)
  • H Oettle et al.

    Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial

    JAMA

    (2013)
  • T Shirasaka et al.

    Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators

    Anticancer Drugs

    (1996)
  • H Ueno et al.

    An early phase II study of S-1 in patients with metastatic pancreatic cancer

    Oncology

    (2005)
  • T Okusaka et al.

    A late phase II study of S-1 for metastatic pancreatic cancer

    Cancer Chemother Pharmacol

    (2008)
  • H Ueno et al.

    Randomized phase III trial of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study

    J Clin Oncol

    (2013)
  • S Sakuramoto et al.

    Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine

    N Engl J Med

    (2007)
  • A Maeda et al.

    Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 in patients with resected pancreatic cancer: Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01)

    Jpn J Clin Oncol

    (2008)
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