S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial

doi:10.1016/S1470-2045(15)00410-6

The Lancet Oncology

Volume 17, Issue 1, January 2016, Pages 99-108

https://doi.org/10.1016/S1470-2045(15)00410-6 Get rights and content

Summary

Background

Although leucovorin enhances the efficacy of fluorouracil, the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer.

Methods

In this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1:1:1) centrally to receive S-1 plus leucovorin (S-1 40–60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m² on day 1, every 2 weeks), or S-1 plus cisplatin (S-1 40–60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m² on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635.

Findings

Between Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28·3–57·8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50·7–79·1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31·4–60·8]) of the 48 patients in the S-1 plus cisplatin group (Fisher's exact test, p=0·84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0·063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0·038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3–4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]).

Interpretation

S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway.

Funding

Taiho Pharmaceutical.

Introduction

Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide.¹ A platinum compound plus fluoropyrimidine has been accepted as the standard first-line treatment for patients with advanced gastric cancer,2, 3, 4 and oral fluoropyrimidines such as capecitabine and S-1 have recently become more favoured than continuous infusion of fluorouracil.4, 5, 6

Leucovorin enhances the efficacy of fluorouracil by stabilising the ternary complex formed between fluorodeoxyuridine monophosphate (FdUMP) and thymidylate synthase. Findings of a meta-analysis⁷ including more than 3000 patients with colorectal cancer showed that leucovorin significantly increased the proportion of patients with a response and overall survival when combined with infusional fluorouracil. In clinical trials of oral fluoropyrimidines combined with leucovorin, uracil and tegafur plus leucovorin was shown to be non-inferior to bolus fluorouracil plus leucovorin in patients with metastatic colorectal cancer,8, 9 whereas adding leucovorin to capecitabine provided little additional benefit despite more adverse events.¹⁰ In view of the fact that the anti-tumour effects and toxic effects of fluoropyrimidines plus leucovorin are time dependent, various treatment schedules of S-1 plus leucovorin have been investigated in several phase 1 and 2 studies.11, 12, 13, 14 The addition of leucovorin to S-1 in a 2-week schedule (1-week on followed by 1-week off) increases the anti-tumour activity of S-1, while toxic effects remained within a manageable range.12, 13 Therefore, this schedule was regarded as the optimum platform for the development of further combination regimens.

Research in context

Evidence before this study

Between Jan 1, 2000, and July 31, 2015, we searched PubMed and the abstracts of major oncology congresses with the keywords including “advanced OR metastatic OR recurrent AND gastric cancer”, and restricted the results to clinical trials and those published in English language. Although triplet regimens combining a fluoropyrimidine (infusional fluorouracil or an oral fluoropyrimidine) and a platinum compound (cisplatin or oxaliplatin) with epirubicin or docetaxel are widely used in the EU and the USA, doublet regimens such as capecitabine plus cisplatin are used worldwide as backbone chemotherapy for combination with investigational new drugs, and S-1 plus a platinum compound (cisplatin or oxaliplatin) is the standard of care for advanced gastric cancer in Japan. Although infusional leucovorin plus fluorouracil with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) is one treatment option, oral fluoropyrimidines such as S-1 or capecitabine combined with oral leucovorin plus a platinum compound have yet to be reported in patients with gastric cancer.

Added value of this study

Our results showed that for patients with advanced gastric cancer, S-1 plus leucovorin was as active as standard treatment with S-1 plus cisplatin, and S-1 plus leucovorin and oxaliplatin showed further promising activity with acceptable toxic effects.

Implications of all the available evidence

Our findings support the further study of S-1 plus leucovorin (TAS-118) and oxaliplatin in a large phase 3 trial in patients with advanced gastric cancer.

Here, we assessed the efficacy and safety of S-1 plus leucovorin and S-1 plus leucovorin and oxaliplatin compared with S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer.

Section snippets

Study design and patients

This multicentre, open-label, randomised, phase 2 clinical trial was done at 25 general hospitals and specialist centres in Japan (appendix p 10). Eligible patients were at least 20 years of age and had a histologically confirmed diagnosis of gastric adenocarcinoma with metastatic or recurrent lesions. At least one measurable lesion as defined by the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) was required.¹⁵ Other inclusion criteria were an Eastern Cooperative Oncology

Results

Between Oct 20, 2011, and Dec 17, 2012, 145 patients were enrolled at 25 institutions in Japan (appendix p 10). Of these patients, 49 were randomly assigned to the S-1 plus leucovorin group, 47 to the S-1 plus leucovorin and oxaliplatin group, and 49 to the S-1 plus cisplatin group (figure 1). Three patients (two in the S-1 plus leucovorin group and one in the S-1 plus cisplatin group) were excluded from the full analysis set. Baseline patient characteristics for the full analysis set are shown

Discussion

In this randomised, phase 2 trial, the proportion of patients with an overall response was higher in the S-1 plus leucovorin and oxaliplatin group compared with the S-1 plus leucovorin and S-1 plus cisplatin groups. Our findings showed that S-1 plus leucovorin and oxaliplatin treatment was better than S-1 plus cisplatin treatment in terms of response, progression-free survival, and overall survival. In view of the results of a previous phase 3 study,³ which reported that S-1 plus oxaliplatin

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Cited by (53)

Schisandrin B suppresses gastric cancer cell growth and enhances the efficacy of chemotherapy drug 5-FU in vitro and in vivo
2022, European Journal of Pharmacology
Citation Excerpt :
For metastatic and recurrent GC, combination chemotherapy becomes an accepted and validated standard treatment in clinical practices (Bang et al., 2017; Okines et al., 2009; Tabernero et al., 2018). 5-fluorouracil (5-FU) and its derivatives (S-1 and Capecitabine), the most wildly used and extensively studied antitumor drug in GC, play a pivotal role in most combination chemotherapy regimens for a long time (Aoyama et al., 2017; Hironaka et al., 2016). For instance, a recent study has proved the obvious advantage of co-delivery of docetaxel and postoperative S-1 for R0 resection of pathologic stage III GC over S-1 alone (Yoshida et al., 2019).
Gastric cancer (GC) is a serious affliction worldwide and remains to be the fourth most common cancer with poor prognosis, especially in advanced stage. Chemotherapy is one of the main therapeutic means. The purpose of this study was to investigate the antitumor effects of Schisandrin B (Sch B) on GC cells both in vitro and in vivo, as well as the synergistic effect with 5-fluorouracil (5-FU), and to preliminarily explore the relevant mechanism of action. Our results showed that Sch B inhibited the growth, migration and invasion of GC cells. Besides, Sch B could effectively inhibit the phosphorylation of STAT3 (signal transducer and activator of transcription 3), induce autophagy, and enhance the efficacy of chemotherapy drug 5-FU in vitro and in vivo. Taken together, the findings indicate that Sch B displays potent antitumor activities. The co-administration of Sch B and 5-FU might be a promising way for future therapy of GC.
TAS-118 plus oxaliplatin in advanced gastric cancer: is it worth it?
2020, The Lancet Oncology
S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial
2020, The Lancet Oncology
Citation Excerpt :
This phase 3 study showed that TAS-118 plus oxaliplatin improved overall survival and was associated with better progression-free survival and overall response rate compared with S-1 plus cisplatin, as a first-line chemotherapy for patients with advanced gastric cancer. This study supports the promising efficacy of S-1 and leucovorin plus oxaliplatin that was shown in our previous phase 2 study.20 The doublet chemotherapies using fluoropyrimidine (fluorouracil, S-1, or capecitabine) and platinum (cisplatin or oxaliplatin) in previous studies showed comparable efficacies (response rate 40–50%, median progression-free survival 5–6 months, and median overall survival 12–15 months),9–12 but the combination of TAS-118 plus oxaliplatin used in this study appears to be associated with the highest results in all efficacy endpoints.
S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer.
We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40–60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m² intravenously on day 1) every 2 weeks, or S-1 (40–60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m² intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593.
Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0–32·8), median overall survival was 16·0 months (95% CI 13·8–18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6–16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69–0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia).
TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients.
Taiho Pharmaceutical and Yakult Honsha.
A multicenter, phase I/II trial of biweekly S-1, leucovorin, oxaliplatin and gemcitabine in metastatic pancreatic adenocarcinoma–TCOG T1211 study
2020, European Journal of Cancer
This phase I/II study evaluated the feasibility and efficacy of S-1, leucovorin, oxaliplatin and gemcitabine (SLOG), a triplet regimen, for treating patients with metastatic pancreatic ductal adenocarcinoma (PDAC).
Patients with chemo-naive, metastatic PDAC were eligible to receive fixed-rate infusion (10 mg/m²/min) of gemcitabine of 800 mg/m² followed by oxaliplatin of 85 mg/m² on day 1 plus oral S-1 and leucovorin (20 mg/m²) twice daily from days 1 to 7 in a 2-week cycle. The dose of S-1 would be escalated from 20, 30, 35 to 40 mg/m2 in a 3 + 3 designed phase I part to determine the maximum tolerated dose (MTD) for phase II study, in which the primary end-point was objective response rate (ORR). The recommended dose of S-1 was from phase I. This trial is registered at ClinicalTrials.gov: NCT01415713.
Seventy-three patients were enrolled. In the phase I study (n = 19), the MTD of S-1 was 35 mg/m² twice daily. Of 54 patients in phase II, the ORR was 40.7% (95% confidence interval [CI], 28%–55%). The median progression-free survival and overall survival were 7.6 (95% CI, 5.6–11.0) and 11.4 (95% CI, 8.1–16.3) months, respectively. The most common grade III/IV adverse event was neutropenia (40.7%). Twenty-four percent of patients had SLOG treatment for more than 1 year. The mean relative dose intensities of gemcitabine, oxaliplatin, and S-1 were 92%, 92% and 89%, respectively.
Biweekly SLOG is a feasible regimen with promising activity and safety profiles. A randomised study comparing SLOG versus modified folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) in advanced PDAC is ongoing (ClinicalTrials.gov: NCT03443492).
TAS-118 (S-1 plus leucovorin) versus S-1 in patients with gemcitabine-refractory advanced pancreatic cancer: a randomised, open-label, phase 3 study (GRAPE trial)
2019, European Journal of Cancer
Citation Excerpt :
Thus, there might be other factors than those expected affecting the efficacy of TAS-118. The safety profiles of TAS-118 and S-1 were consistent with previous reports of S-1/LV or S-1 alone [10–12], and both treatments were well tolerated. The toxicities of TAS-118 were well managed by appropriate dose reduction.
In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS).
This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40–60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40–60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS.
A total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82–1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67–0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups.
TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1.
Development and validation of nomograms for predicting overall survival and cancer-specific survival in elderly patients with locally advanced gastric cancer: a population-based study
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ArticlesS-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and patients

Results

Discussion

Lancet Oncol

Ann Oncol

Ann Oncol

Lancet Oncol

Ann Oncol

Eur J Cancer

GLOBOCAN 2012: cancer incidence and mortality worldwide

Capecitabine and oxaliplatin for advanced esophagogastric cancer

N Engl J Med

Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis

J Clin Oncol

Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer

J Clin Oncol

Articles
S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial