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A phase II trial of oxaliplatin plus S-1 as a first-line chemotherapy for patients with advanced
gastric cancer
YANG Lin, SONG Yan, ZHOU Ai-ping, QIN Qiong, CHI Yihebali, HUANG Jing and WANG Jin-wan
Department of Medical Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing
100021, China
Correspondence to: Professor Lin Yang
No. 17, Panjiayuannanli, Chaoyang District, Beijing 100021, ChinaTel: +86-10-87788118; Fax: +86-10-67734107;
Mobile: +86 13681015148;
E-mails: [email protected]; [email protected]
1
ABSTRACT
Background Palliative chemotherapy has been shown to have a survival benefit for patients with recurrent or
metastatic gastric cancer. We conducted a phase II trial to determine the efficacy and safety of S-1 plus oxaliplatin
(SOX regimen) as a first-line chemotherapy for patients with unresectable locally advanced or metastatic gastric
cancer.
Methods Eligible patients had measurable lesions and no previous history of chemotherapy (except adjuvant
chemotherapy). Oxaliplatin was administered intravenously at a dose of 130 mg/m 2 on day 1. S-1 was administered
orally at doses of 80, 100, or 120 mg/day according to body surface areas of <1.25, 1.25–1.5 or >1.5 m2,
respectively; the total dose was divided into two daily doses on days 1–14. Treatments were repeated every 3 weeks
until disease progression or intolerable toxicity occurred.
Results Forty-three patients were enrolled in the study. All were assessable for efficacy and adverse events. The
objective response and disease control rates were 55.8% and 76.7%, respectively. The median follow-up time was
16.5 months. The median progression-free survival time was 7 months (95% confidence interval (CI), 5.8–8.2
months) and the median overall survival time was 16.5 months (95% CI, 9.7–23.3 months). The 1-year survival rate
was 54.2%. Major adverse reactions were grade 3/4 neutropenia (9.3%) and thrombocytopenia (20.9%).
Conclusions The SOX regimen with oxaliplatin at a dose of 130 mg/m2 was found to be effective and safe as a firstline chemotherapy in Chinese patients with advanced gastric cancer.
Keywords: stomach neoplasms; drug therapy; oxaliplatin; S-1
2
INTRODUCTION
Gastric cancer is the second leading cause of cancer death worldwide.1 Currently, surgical resection is the only
treatment that can cure gastric cancer. Unfortunately, most patients with this malignancy have unresectable locally
advanced or metastatic disease at diagnosis, or develop a recurrence after surgery. 2 Systemic chemotherapy may
prolong survival time, relieve cancer-related symptoms, and improve quality of life. 3-5 Although it is associated with
treatment-related toxicities, combination chemotherapy has been shown to improve survival relative to monotherapy
and to achieve a higher response rate at the cost of higher toxicity. 6,7 At present, fluorouracil plus platinum
combination chemotherapy is the most commonly used, but there is still no standard regimen for first-line treatment
of advanced gastric cancer.
S-1 is a novel oral fluoropyrimidine that consists of tegafur (5-fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4-dione
[FT]), gimeracil (5-chloro-2,4 hydropyridine [CDHP]) and oteracil (potassium oxonate [OXO]) in a molar ratio of
1:0.4:1.11 FT is the prodrug for cytotoxic fluorouracil (FU). CDHP is a competitive inhibitor of dihydropyrimidine
dehydrogenase, the initial and rate-limiting enzyme of 5-FU degradation. CDHP is used to raise and maintain
effective 5-FU plasma concentrations by inhibiting its metabolism. 12 OXO reduces gastrointestinal toxicity induced
by phosphorylated 5-FU by inhibiting gastrointestinal orotate phosphoribosyltransferase, the principal enzyme that
directly converts 5-FU to the active chemotherapeutic metabolite 5-fluoro-2'-deoxyuridine 5'-monophosphate.13 A
number of studies have reported that S-1 as a single agent has significant activity against gastric cancer, with
response rates (RR) of 26–49% and favorable safety profiles. The SPIRITS trial reported that S-1 plus cisplatin (SP
regimen) achieved an overall survival (OS) time of ˃1 year, 14 and thus this regimen has become the standard firstline chemotherapy for unresectable or recurrent gastric cancer in Japan. A phase III trial conducted in China (SC101) demonstrated that the SP regimen had an improved time to failure, and also achieved an improved OS
compared with 5-FU plus cisplatin (FP); in addition, the SP regimen was demonstrated to be significantly superior
to S-1 alone.15
3
Oxaliplatin is a third-generation platinum compound that was developed to improve ease of administration and
tolerability as compared with cisplatin. The noninferiority of oxaliplatin-based regimens relative to cisplatin-based
regimens has been demonstrated in two phase III trials. 16-18
We conducted the current phase II study involving patients with advanced gastric cancer to evaluate the efficacy and
safety of combination treatment with S-1 and oxaliplatin (SOX regimen) as first-line therapy.
METHODS
Patients
Forty-three patients from the Cancer Hospital of the Chinese Academy of Medical Sciences with evidence of gastric
cancer were enrolled in the study from April 2011 to June 2012. Eligible patients met all of the following criteria:
the presence of histologically confirmed unresectable locally advanced or metastatic gastric or gastroesophageal
junction adenocarcinoma, as well as at least one measurable lesion using the Response Evaluation Criteria In Solid
Tumours (RECIST) Criteria; anticipated life expectancy >3 months; age >18 years; an Eastern Cooperative
Oncology Group (ECOG) performance status of 0–2; adequate hematological, renal, and hepatic functions, as
defined by an absolute granulocyte count of ≥1.5×109/L, a platelet count of ≥100×109/L, a hemoglobin level of ≥9.0
g/dL, a serum creatinine level of ≤1.4 mg/dL, a serum bilirubin level of ≤1.8 mg/dL, and an aspartate
aminotransferase/alanine aminotransferase level of ≤2 times the upper limit of the normal level. Patients that had
undergone previous adjuvant chemotherapy were eligible if they had completed treatment ˃6 months prior to
enrollment in this study. Additionally, patients had to have the following characteristics: no central nervous system
metastases; no active infection; no serious or uncontrolled concurrent medical illness; and no history of other
malignancies. Patients were required to provide written informed consent prior to participation in the study. This
prospective clinical trial (NCT01531452) was approved by the local ethical committee of the Cancer Hospital of the
Chinese Academy of Medical Sciences. It has been registered at clinicaltrial.gov.
Treatment plan and dose modification
S-1 was administrated orally at doses of 80, 100, or 120 mg/day, according to body surface areas of <1.25, 1.25–1.5,
or >1.5 m2, respectively; administration involved division of the total dose into two daily doses, given after meals on
4
days 1–14, with a 7-day interval. Oxaliplatin was administrated at a dose of 130 mg/m2 over 2 h by intravenous drip
on day 1, every 3 weeks. Preventive antiemetic drugs were administered before oxaliplatin infusion.
Dose modifications were made to the S-1 plus oxaliplatin regimen according to hematological, gastrointestinal, or
neurological toxicity, based on the most severe grade of toxicity occurring during the previous cycle. The dose of S1 was reduced from 120 to 100 mg/day or from 100 to 80 mg/day, in cases involving NCI-CTC grade 3 diarrhea,
stomatitis, or dermatitis. The oxaliplatin dose was reduced by 25% in subsequent cycles in cases in which persistent
paresthesias between cycles, or paresthesias with functional impairment, persisted for more than 7 days. Only two
dose reductions were allowed per patient.
Treatment was continued until disease progression or unacceptable toxicities developed, or until a patient refused
further treatment. The relative dose intensity is the ratio of the actual dose intensity of the chemotherapy to the
planned dose intensity. The planned dose intensity unit was expressed as mg/m2/week. The S-1 and oxaliplatin
planned dose intensities were 373.3 and 43.3 mg/m2/week, respectively.
Follow-up and evaluation
Baseline evaluation included: the patient’s medical history; a complete physical examination; a urine pregnancy test
(for women); a general status score; a blood cell count; blood chemistry; analysis of tumor markers; recordings of
medical co-morbidities; a chest X-ray/computed tomography (CT) scan; and imaging of the abdomen/pelvic region
using either CT or magnetic resonance imaging. During treatment, CT scans were carried out and tumor markers
were measured every 6 weeks.
Response to treatment was assessed using the RECIST guidelines and toxicity was assessed using the National
Cancer Institute Common Toxicity Criteria version 3.0 (www.cancer.gov/). Oxaliplatin-specific neurotoxicity was
categorized as: grade 1, paresthesias or dysesthesias of short duration, but resolving prior to the next cycle; grade 2,
paresthesias persisting between cycles (2 weeks); and grade 3, paresthesias interfering with neurological function.
Statistics and sample size
The primary endpoint of this study was the objective response rate (ORR), while the secondary endpoints were OS,
5
progression-free survival (PFS), and safety. A two-stage Simon's optimal design was used. The first stage required
at least 18 or more patients out of 34 to have a confirmed partial and complete response assuming P1=0.6 and P0=0.4,
with α=0.05 and β=0.2, before proceeding to the second stage. In the second stage, five assessable patients could be
added and if a total of 22 or more patients achieved a confirmed objective response, then the primary endpoint
would have been met. A follow-up loss rate of 10% was assumed, which means an enrollment of 43 patients was
needed. The 95% confidence interval (95% CI) of the ORR was calculated. OS and PFS were calculated using the
Kaplan–Meier method. All statistics tests were two sided, and a P value of <0.05 was considered as being
statistically significant. PFS was calculated from the date of initiation of chemotherapy to the date of disease
progression, death, or final follow-up. OS was calculated from the date on which the chemotherapy was initiated to
the date of death or final follow-up. All analyses were carried out using an SPSS software package (SPSS 17.0 Inc.,
Chicago, IL, USA).
RESULTS
Patient characteristics
Patient characteristics are presented in Table 1. All patients were evaluable regarding treatment safety and efficacy.
Ten patients had unresectable locally advanced disease, and 33 patients had metastatic disease. Fourteen of the 43
patients had gastroesophageal junctional carcinoma. Six of the 43 enrolled patients had undergone radical resection
of the primary gastric or gastroesophageal junction tumors. The most common metastatic organs and the number of
metastatic sites are detailed in Table 1. Most patients (93%) had a good performance status (ECOG, 0–1).
Treatment response
The ORR was 55.8% (95% CI, 41.0–70.6%) after a median of five (range, 2–13) cycles of treatment. No complete
response was observed. Nine patients had stable disease and 10 patients had disease progression. The disease control
rate was 76.7% (95% CI, 70.3–83.1%). Treatment outcomes are detailed in Table 2. One patient was still receiving
S-1 alone as the study closed. The most common causes of treatment discontinuation were disease progression
(23/43 [53.5%]), adverse events (1/43 [2.3%]), and refusal to continue treatment (9/43 [20.9%]).
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PFS and OS
As of April 2013, four patients were lost to follow-up. The survival time of these four patients was set at the last
follow-up time at which the patient was evaluated. Among the 43 patients, the median PFS was 7 months (95% CI,
5.8–8.2 months; Figure 1). After a median follow-up time of 16.5 months, the median OS was 16.5 months (95% CI,
9.7–23.3 months; Figure 2). The 1-year survival rate was 54.2%.
Treatment exposure and safety
The median number of cycles for the SOX regimen was five (range, 2–8). The relative dose intensity of oxaliplatin
and S-1 were 95% and 86.2%, respectively. After disease progression, 68.6% (24/35) of patients accepted secondline chemotherapy. Surgery was performed in nine patients after a response was achieved.
All 43 patients were evaluable for treatment safety. To reduce toxicity, oxaliplatin doses were reduced at least once
in five patients (11.6%). Three patients (7%) experienced an S-1 dose reduction (one patient had one and two
patients had two dose reductions). The treatment toxicity profile is detailed in Table 3. No patient had febrile
neutropenia. All non-hematological toxicities were grades 1–2. Common non-hematological toxicities are also given
in Table 3. No treatment-related deaths occurred.
DISCUSSION
Although numerous new drugs (irinotecan, paclitaxel, docetaxel, oxaliplatin, capecitabine, and S-1) have emerged
and are now widely used in the treatment of gastric cancer, only limited improvement in survival time has been
achieved.8,14-19 Previous studies have reported an RR of 25–54%, a PFS of 2.9–7 months, and a median survival time
of 8.6–13 months. Three-drug combination regimens have not been widely used because of severe hematological
toxicities, although these regimens have improved efficacy. At present, the most commonly used two-drug
combination is still fluorouracil plus platinum.
Japanese studies have reported that the SP regimen is well tolerated and grade 3/4 adverse events have included
neutropenia (40%), anemia (26%), and decreased appetite (30%). 14 A phase III clinical trial was performed in China
comparing the efficacy of S-1 monotherapy, and the SP and FP regimens. The ORR for S-1 alone, and the SP and
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FP regimens was 24.7%, 37.8%, and 19.2%, respectively; the time to progression (TTP) was 4.1, 5.2, and 2.8
months, respectively and the OS was 8.8, 14.4, and 10.1 months, respectively. Grade 3/4 neutropenia and
thrombocytopenia rates were 17.1% and 6.6%, respectively, and the overall incidence of grade 3/4 gastrointestinal
toxicity was low.15 However, there is a significant difference between Eastern and Western patients in terms of
tolerance to S-1. A phase I study carried out in the USA found that the maximum tolerated dose for S-1 was 50
mg/m2/day using the SP regimen. Such differences in tolerance may be attributed to genetic polymorphisms of
cytochrome P450.20 In a clinical trial conducted in the USA involving advanced gastric cancer, the ORR, PFS, and
OS using the SP regimen was 29.1%, 4.8 months, and 8.6 months, respectively.21As compared with the FP regimen,
the OS was not prolonged using the SP regimen, but safety was improved. Reductions were observed in grade 3/4
neutropenia (32.3% vs. 63.6%), mucositis (1.3% vs. 13.6%), and treatment-related deaths (2.5% vs. 4.9%).21
Oxaliplatin is not inferior to cisplatin; patient hydration is not required after administration of the drug, the
hospitalization time is shorter, and gastrointestinal reactions, nephrotoxicity, and ototoxicity are all lower. In our
trial involving 43 patients that received the SOX regimen, with a median follow-up time of 16.5 months the RR was
55.8%, the median PFS was 7 months, and the median OS was 16.5 months. The most common grade 3/4
hematological toxicity was thrombocytopenia (20.9%) and neutropenia (9.3%). The rate of oxaliplatin-specific
neurotoxicity was 51.2%. There was no grade 3/4 neurotoxicity and no other grade 3/4 non-hematological toxicities.
These findings suggest that the SOX regimen is well tolerated. Recently, a Japanese phase III randomized controlled
study found that the SOX regimen is not inferior to the SP regimen in terms of PFS, but had a better toxicity
profile.21 In comparing the SOX and SP regimens, grade 3/4 neutropenia was 19.5% and 41.5%, respectively and
grade 3/4 thrombocytopenia was 9.5% and 10.4%, respectively. However, the SOX trial was associated with a
higher incidence of hepatic damage and neurological toxicity. The SP regimen described in the report was associated
with more hyponatremia and renal dysfunction. These findings suggest that the SOX regimen may be an alternative
to first-line standard treatment for advanced gastric cancer in Japan.22
Dosage and administration schedules have differed in the various published studies. In studies involving advanced
colorectal cancer, the recommended SOX dosages, which are well tolerated, are 130 mg/m2 for oxaliplatin and 80
mg/m2 for S-1, administered for 14 days with a 7-day break every 3 weeks.23-25 Therefore, we chose this regimen for
8
our advanced gastric cancer patients in the current phase II trial. Up until now, there have been four previously
published phase II studies regarding the SOX regimen in the treatment of advanced gastric cancer reported in the
literature. The administration of oxaliplatin at a dose of 130 mg/m2 every 3 weeks for one cycle has been reported in
only one previous clinical trial.26 Oxaliplatin given at a dose of 100 mg/m2 every 3 weeks was used in two studies,
and a bi-weekly administration of oxaliplatin was used in an additional study. 27-29 The ORR for these four trials was
53.7–59%, with a median TTP of 4.6–6.6 months, and a median OS of 7.8–16.5 months.25-28 The incidence of grade
3/4 thrombocytopenia (20.9%) in our study was higher than those observed in previous studies involving regimens
using oxaliplatin at a dose of 100 mg/m2/day. Although there was no bleeding due to thrombocytopenia,
thrombocytopenia is the most common cause for treatment delay and dose reduction. Further investigation is
necessary to determine the optimal dose of oxaliplatin for future clinical administration when combined with a fixed
dose of S-1 in the SOX regimen.
In conclusion, the SOX regimen is an effective, well-tolerated, and conveniently administrated first-line therapy for
patients with advanced gastric cancer.
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Table 1. Patients and treatment characteristics
Characteristic
No. of patients
Percentage(%)
43
100
14
29
32.6
67.4
31
12
72.1
27.9
Total
Location of the primary tumor
Gastroesophageal junction
Gastric
Gender
Male
Female
Age, years
Median (Range)
BSA, per m2
Median (range)
Performance status (ECOG)
0
1
2
Primary tumor
Yes
No
Sites of metastasis
Lymph node
Liver
Lung
Peritoneum
Others
No. of metastatic sites
1
≥2
Prior adjuvant chemotherapy
Yes
Prior 5-FU
Prior DDP
Total No.of treatment cycles
Median (range)
62（28-76）
1.7（1.3-2.0）
1
39
3
2.3
90.7
7
37
6
86
14
36
13
4
7
7
83.7
30.2
9.3
16.3
16.3
26
17
60.5
39.5
14
14
11.6
4.7
6
5
2
240
5（2-13）
12
Table 2. Response to treatment (N=43)
Type of response
Complete
Partial
Confirmed ORR
Stable disease
Progression of disease
Disease control rate
No. of patients
0
24
24
9
10
33
%（95%CI）
0
55.8
55.8（41.0-70.6 ）
20.9
23.3
76.7（70.3-83.1 ）
Table 3. Treatment toxicity
Type
Hematologic
Anemia
Neutropenia
Thrombocytopenia
Non-hematologic
Nausea
Vomiting
Anorexia
Diarrhea
Mucositis
Neuropathy
Fatigue
Skin Pigmentation
HFS*
Allergy
Hypokalemia
Grade (N)
Percentage
Percentage
1
2
3
4
All %
Grade 3/4 %
18
15
6
11
19
9
0
3
7
0
1
2
67.4
88.3
55.8
0
9.3
20.9
29
15
30
8
5
20
22
15
3
1
1
11
12
5
0
0
2
2
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
93
62.8
81.4
18.6
11.6
51.2
55.9
58.1
7
2.3
2.3
0
0
0
0
0
0
0
0
0
0
0
*HFS: Hand and foot syndrome
13
14
作者单位（杨林，宋岩，秦琼，依荷芭丽.迟，黄镜，王金万）
中国医学科学院肿瘤医院肿瘤研究所 内科
北京
100021
通讯作者：杨林
通信地址：
北京市朝阳区潘家园南里 17 号
肿瘤医院内科
电话：010-87788118；传真：010-67734107；手机：13681015148
Email: [email protected]
[email protected]
Conflict of interest statement
All authors declared no conflicts of interest.
This study was presented at the 10th International Gastric Cancer Congress (IGCC 2013)
Verona, Italy, 2013 (www.10igcc.com)
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