S-1 monotherapy as second line chemotherapy in advanced gastric cancer patients previously treated with cisplatin/infusional fluorouracil

Abstract

The treatment choice of advanced gastric carcinoma after failure from first-line therapy is quite limited. To evaluate the efficacy and toxicity of S-1 monotherapy in patients with advanced gastric cancer after failure of first line cisplatin and fluorouracil combination (CF). S-1 monotherapy as a second line treatment was given to the patients who had failed to CF combination in SC-101 study. The efficacy and toxicity of S-1 monotherapy were evaluated exploratory. The results indicated that forty-one patients received S-1 as a second line therapy after disease progression. The overall response rate and disease control rate were 14.6% and 41.5%, respectively. The median progression free survival (PFS) was 5.1 months (range: 2.9~6.2 month). The median overall survival time was 6.4 months. The survival rates at 6 month and 1 year were 56% and 7.3%, respectively. Grade 3/4 adverse events were uncommonly occurred, including anemia (2.4%), neutropenia (2.4%), thrombocytopenia (4.9%) and rash (2.4%). There were no unexpected or life-threatening toxicities. Only one patient experienced dose reduction due to grade 3 rash. In conclusion, S-1 monotherapy provided a mild response rate and overall survival, and a favorable toxicity profile in the second line setting after the first line failure to cisplatin and fluorouracil combination.

Introduction

Combination chemotherapy was reported to be superior to the best supportive care in the management of advanced gastric cancer (AGC) [1-3]. The various combination chemotherapy regimens as first-line treatment showed response rates of 35-45%, and a median progression-free survival (PFS) of 5-6 months. And the regimen of cisplatin and fluorouracil combination was regarded as a referenced chemotherapy in the fist line treatment. Studies of second line chemotherapy reported an overall survival (OS) ranging from 5 to 9 months and a progression free survival ranging from 2 to 4 months [4-8]. There is no standard second line treatment for these patients up to now. Although some new agents, such as taxanes and CPT-11 have shown encouraging anti-tumor activity in advanced gastric cancer patients, these regimens are inevitably accompanied by substantial toxicities, which reduce their value as a palliative treatment, especially in the second line treatment in patients with relative poor clinical condition. Therefore, the need for new regimens with improved efficacy and safety is increasing for patients who have failed first line treatment.

S-1 is a newly developed oral fluoropyrimidine that composed of a mixture of tegafur, 5-chloro-2, 4-dehydroxypyridine and potassium oteracil in a molar ratio of 1:0.4:1 [9]. In several trials conducted in Japan, S-1 monotherapy demonstrated promising activity which was comparable to combination chemotherapy in advanced gastric cancer, and it has been one of the preferred agents for gastric cancer [10,11]. Moreover, it has a safety profile, which is favorable compared with other oral fluoropyrimidines used in gastric cancer.

Based on these observations, S-1 may be a substitute for the combined chemotherapy as a second line treatment in gastric cancer patients, especially in those with poor general condition. Thus, we conducted a prospective study to evaluate the feasibility of S-1 as a second line approach in patients with advanced gastric cancer. S-1 was given to those patients who developed disease progression after cisplatin/fluorouracil (CF) combination in clinical trial SC-101 which comparing S-1 vs cisplatin/S-1 vs cisplatin/fluorouracil as a first line treatment for advanced gastric cancer.

Materials and methods

Eligibility

S-1 monotherapy as post first line therapy was allowed to treat patients who were refractory to cisplatin/fluorouracil combination in the setting of protocol of SC-101. SC-101 (clinical study registered number: NCT 00202969) was a randomized phase III trial comparing efficacy of cisplatin/fluorouracil (CF) vs cisplatin/S-1 vs S-1 alone in chemo-naïve advanced gastric cancer patients in China from 2005 to 2007. S-1 was allowed to be given to the patients who developed disease progression after the first line CF combination. All patients who failed the first line therapy studied in current study should have locally advanced or metastatic, histologically confirmed gastric adenocarcinoma, with at least one measurable lesion according to the RECIST Criteria (Response Evaluation Criteria in Solid Tumor Criteria). All patients had to be older than 18 years, with an ECOG performance status 0-2, adequate hematological, renal and hepatic function. Patients were excluded if they had brain or leptomeningeal metastases, multiple bone metastases, severe comorbid conditions. Patients who were taking drugs with probable potential interactions with S-1 (Sorivudine, flucytosine, allopurinol, and phenytoin) were also excluded.

Treatment

Efficacy and safety of S-1 as a second line therapy were evaluated exploratory after the failure to CF combination in SC-101 study. S-1 was administered orally twice daily after meals. Three initial doses of S-1 were established according to body surface area (BSA) as follows: BSA < 1.25 m², 80 mg/day; 1.25 m² < BSA < 1.5 m², 100 mg/day; and 1.5 m² < BSA, 120 mg/day (Table 1). One course consisted of consecutive administration for 28 days followed by 14 days’ rest. Dose increment was allowed once if patient is well tolerated to the initial dose and the dose may be increased only one time. Dose reduction was allowed when grade 4 hemotological toxicities or grade 3/4 severe non-hemotological toxicities occurred during treatment according to the doctors’ discretion (Table 2). When toxicity resolved to less than grade 1, the reduced dose was used for the following cycles.

Table 1.

S-1 dosage

S-1 Dose	Dosage (mg) (every 12 h)	Total Daily Dose (mg)
40 mg/m2
BSA < 1.25 m2	40	80
BSA = 1.25 < 1.5 m2	50	100
BSA ≥ 1.5 m2	60	120

Table 2.

Dose modifications allowed for S-1

Arm	Drug	Dose Increment		Initial Dose		Dose Reduction & Suspension
Arm A: S-1	S-1	50 mg	←	40 mg	→	suspension
		60 mg	←	50 mg	→	40 mg	→	suspension
		75 mg	←	60 mg	→	50 mg	→	40mg	→	suspension

Statistical considerations

The primary end point of this study was overall survival, and the second end points were response rate and toxicity. Response was evaluated every two cycles with RECIST Criteria Version 1.1 (Response Evaluation Criteria in Solid Tumor Criteria Version 1.1), and was confirmed after at least 28 days if a partial or complete response occurred. CTCAE (Common Terminology Criteria for Adverse Event) version 3.0 was used to evaluate safety. Survival estimates were calculated using the Kaplan-Meier method. Overall survival (OS) was calculated from the beginning date of S-1 administration to the date of death from any cause, or to the date of last follow-up when data were censored. Progression-free survival (PFS) was calculated from the beginning date of S-1 administration to the first observation of disease progression or death from any cause. If a patient had not progressed or died, PFS was censored at the time of last follow-up.

Results

Patient population

All of the forty-one patients who experienced disease progression in cisplatin/fluorouracil group received S-1 monotherapy. Although fifteen patients experienced early progression after S-1 administration and stopped taking the drug, they were all evaluated for efficacy and toxicity. Patient characteristics are listed in Table 3.

Table 3.

Patient and cancer baseline characteristics

Characteristic	No.	%
Female	9	22
Male	32	78
Age (ys)	38-77
Median	52
PS
0	1	2.4
1	30	73.2
2	10	24.4
Gastrectomy status
Absent	20	48.8
Present	21	51.2
Liver metastasis
No	28	68.3
Yes	13	31.7
Lung metastasis
No	40	97.6
Yes	1	2.4

Efficacy

A median of three cycles (ranging from 1 to 9) was administered to each patient. The response of S-1 monotherapy as a second line treatment was showed in detail (Table 4). The response rate and the disease control rate in these 41 patients were 14.6% and 41.5%, respectively. After a median follow-up time of 4.5 months, the median PFS and OS were 5.1 months (Figure 1) and 6.4 months (Figure 2), respectively. The overall survival rates at 6 month and 1 year were 56% and 7.3%, respectively.

Table 4.

Efficacy of S-1 in second line therapy

	N	Incidence (%)
CR	1	2.4%
PR	5	12.2%
SD	11	26.8%
PD	24	58.5%

Figure 1.

Progression Free Survival of S-1 2^nd line therapy.

Figure 2.

Overall Survival of S-1 2^nd line therapy.

Safety

All 41 patients received at least one dose of S-1 treatment were subjected to safety analysis. The most common treatment related adverse events were pigmentation disorder (28.8%), neutropenia (24.4%), nausea (17.1%), anemia (14.6%), vomiting (12.2%), diarrhea (12.2%) and fatigue (12.2%). However, grade 3/4 adverse events were uncommonly occurred, including anemia (2.4%), neutropenia (2.4%), thrombocytopenia (4.9%) and rash (2.4%). Only one patient experienced dose reduction due to grade 3 rash.

Discussion

To the best of our knowledge, this is the first prospective report on S-1 monotherapy following the failure of the first line combination of cisplatin and fluorouracil in patients with advanced gastric cancer. The present study shows that the overall objective response rate and disease control rate of S-1 monotherapy are 14.6% and 41.5%, respectively. The progression-free survival is 5.1 months and median survival is 6.4 months. It was reported that response rate of the second line treatment for advanced gastric cancer was ranging between 11% and 26.5%, and median overall survival was ranging between 5.1 and 7.2 months [12-14]. Some other reports with drugs of new generation showed a little better response rate and survival time profile [15,16]. The response rate and survival time of S-1 in our study were comparable with several other second line treatments especially monotherapy.

Since rare survival benefit was shown for the second line therapy of advanced gastric cancer, no regimen has been recommended as a salvage option. In practice, four kinds of active agents including fluoropyrimidine, platinum, irinotecan and taxanes, might begin to hope different combination alternatives in this setting. There have been many reports of second line chemotherapy. Ueda reported a retrospective study, in which 32 patients treated with CPT-11 (70 mg/m²) + cisplatin (80 mg/m²) repeated every 4 weeks showed a response rate of 25%, and median survival time of 9.4 months [15]. Hironaka reported that weekly paclitaxel (80 mg/m², repeated weekly three times for 4 weeks) yielded a response rate of 23%, and median survival time of 5 months in 38 patients who were previously treated with S-1, cisplatin + fluoropyrimidine, or fluorouracil + methotrexate [16]. Therefore, it is believed that second line chemotherapy with irinotecan or taxanes can yield tumor shrinkage in some patients. However, these studies also showed an unfavorable toxicity profile for these patients who failed to the first line treatment. The incidences of Grade 3/4 neutropenia have been reported to be 81% and 32%, for CPT-11 + cisplatin and weekly paclitaxel, respectively. The safety analysis from our study showed that the S-1 monotherapy at a dose of 40 mg/m² bid was well tolerable as a second line chemotherapy. In current study, grade 3/4 adverse events were uncommonly occurred, including anemia (2.4%), neutropenia (2.4%), thrombocytopenia (4.9%) and rash (2.4%). There were no unexpected or life-threatening toxicities. Only one patient experienced dose reduction due to grade 3 rash.

Although S-1 is well tolerated, it is considered that the ability to produce tumor shrinkage in the second-line setting might not be as strong as CPT-11 or taxanes based combinations. The response rate and disease control rate in our study were 14.6% and 41.5%, respectively. This means that more than half of the patients receiving second line chemotherapy showed progressive disease at the first evaluation. In fact, there are 15 patients developed early disease progression after S-1 administration.

In conclusion, S-1 monotherapy provided mild response rate and overall survival time, and a favorable toxicity profile in the second line setting after failure of cisplatin and fluorouracil combination. It is easily administered and might be an option for those patients with poor clinical condition.

Disclosure of conflict of interest

None.