This study was designed to determine the efficacy and safety of FOLFOX-4 chemotherapy as a salvage treatment for patients with advanced gastric cancer (AGC).
The AGC patients with an ECOG performance status of 0~1 and progressive disease after prior treatments were registered onto this phase II trial. The patients received oxaliplatin (85 mg/m2 on day 1), leucovorin (200 mg/m2 on days 1 and 2) and 5-fluorouracil (400 mg/m2 as a bolus and 600 mg/m2 as a 22-hour infusion on days 1 and 2) every 2 weeks.
For the 42 treated patients, a total of 228 chemotherapy cycles (median: 5, range: 1~12) were administered. Twenty-nine patients (69%) received FOLFOX-4 chemotherapy as a third-(50%) or fourth-line (19%) treatment. On the intent-to-treat analysis, 9 patients (21%) achieved a partial response, which was maintained for 4.6 months. The median progression-free survival and overall survival were 3.0 months and 6.2 months, respectively. The frequently encountered toxicities were neutropenia and gastrointestinal side effects, including anorexia. Although there was one possible treatment-related death, the toxicity profiles were generally predictable and manageable.
Salvage chemotherapy with FOLFOX-4 is an effective and tolerable regimen for those heavily pretreated AGC patients who have a good performance status.
Gastric cancer is the most common cancer and the third leading cause of cancer death in Korea (
Oxaliplatin is a third generation platinum compound with the 1,2-diaminocyclohexane (DACH) carrier ligand. Oxaliplatin has shown efficacy against many tumor cell lines, including some that are resistant to cisplatin and carboplatin (
With this background, we conducted a phase II study to determine the effectiveness and safety of FOLFOX-4 when this is used as a salvage regimen for previously treated patients with advanced or metastatic gastric cancer.
All the study patients were required to fulfill the following eligibility criteria: (1) histologically proven gastric adenocarcinoma; (2) tumor progression after prior chemotherapy for metastatic or locally advanced disease; (3) >4 weeks had passed since undergoing prior chemotherapy; (4) no previous exposure to oxaliplatin; (5) measurable lesion that can be accurately measured in at least one dimension (longest diameter ≥1 cm with spiral CT); (6) age more than 18 years; (7) Eastern Cooperative Oncology Group (ECOG) performance status ≤1; (8) adequate bone marrow (absolute neutrophil count ≥1,500/mL, platelet count ≥100,000/mL); (9) adequate hepatic function [bilirubin level ≤1.25 upper limit of normal (ULN), hepatic transaminase ≤2.5 ULN; in the presence of hepatic metastases, bilirubin level ≤1.5 ULN and hepatic transaminase ≤5 ULN]; (10) adequate renal function (serum creatinine <1.5 mg/dL) and (11) estimated life expectancy of at least 3 months. Patients were excluded from study if they had peripheral neuropathy of any grade, central nervous system metastases and an uncontrolled comorbid illness or other malignancy. This study protocol was reviewed and approved by the Gil Medical Center (Incheon, Korea) institutional review board. Written informed consent was obtained from all the patients.
The patients received oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1, and LV 200 mg/m2 as a 2-hour infusion followed by bolus 5-FU 400 mg/m2 and a 22-hour infusion of 5-FU 600 mg/m2 on days 1 and 2. This treatment was repeated every 2 weeks. Treatment was continued until disease progression or unacceptable toxicity occurred or the patient declined further treatment.
The dose modifications were based on the hematologic parameters and the degree of non-hematologic toxicities. A physical examination, chest x-ray, complete blood counts and biochemical tests were performed before each chemotherapy cycle. The toxicity grading was based on the National Cancer Institute Common Toxicity Criteria (version 3.0). Chemotherapy was delayed until recovery if the neutrophils decreased to <1,500/mm3 or the platelets decreased to <100,000/mm3 or for the patients with significant persisting non-hematologic toxicity. The dose of 5-FU was reduced by 25% when grade 3/4 diarrhea, stomatitis or dermatitis occurred. The oxaliplatin was reduced by 25% for the patients with grade 3/4 neutropenia. For the cases of persistent (14 days or longer) painful paresthesia or functional impairment, the oxaliplatin was omitted from the regimen until recovery.
The tumor responses were classified according to the Response Evaluation Criteria in Solid Tumors (RECIST). The response was evaluated based on the findings of a computed tomography (CT) scan with each assessment being done using the same imaging technique as that at baseline. The clinical responses were assessed every 3 courses of chemotherapy or earlier in the case of clinical deterioration.
The primary end point of the study was the objective response rate. The secondary end points consisted of toxicity, progression-free survival (PFS) and overall survival (OS). Forty evaluable patients were required for a single-stage phase II clinical study with assuming that the expected overall response rate would be 25% and the threshold rate was 10% (alpha and beta-errors set at 0.1).
Survival analysis was performed by the Kaplan-Meier method. PFS was calculated from the date of the beginning of treatment to that of clinical progression. OS was defined as the interval between the date of the beginning of treatment and the date of death or the last follow-up appointment. Cox's proportional hazard method was used for assessing the independent prognostic factors. Statistical significance was calculated at the 95% confidence interval (p<0.05). All the analyses were performed using SPSS for windows 15.0 (SPSS Inc., Chicago, IL).
A total of 42 patients were enrolled in the study between August 2004 and March 2007. The patient characteristics are listed in
Thirty-eight patients were evaluable for response. The response was not assessable in four patients due to follow-up loss (n=1), the patient's refusal for further treatment after the first cycle (n=1) and death of patients before the completion of the second cycle (n=2). According to the intent-to-treat principle, 9 partial responses were observed, giving an overall response rate of 21% [95% confidence interval (CI), 8 to 34%]. The median duration of the response was 4.6 months. Taking into account the 14 patients who had stable diseases, 23 patients (55%) achieved clinical benefit, which was defined as a partial response or stable disease. There was no significant difference in the response rate between the patients who had previously received platinum-based regimens vs. the patients who had not (29 vs. 16%, respectively, p=0.446). The main reasons for treatment discontinuation were disease progression (67%), patient refusal (14%) and toxicity (12%). After the median follow-up duration of 16.6 months, the median PFS and OS were 3.0 months (95% CI, 2.0 to 4.0 months) and 6.2 months (95% CI, 4.3 to 8.1 months), respectively (
We conducted univariate analysis of the baseline characteristics such as age, gender, ECOG performance status, the response to previous therapy, the number of previous chemotherapy regimes the patient had undergone, having undergone previous cisplatin-based therapy and the number of organs with metastatic tumor.
As shown in
Forty-two patients received a total of 228 cycles of chemotherapy, with a median number of five cycles per patient (range: 1 to 12). The frequencies of the treatment-related hematological and non-hematological toxicities are listed in
Chemotherapy has been shown to improve patient survival as compared with best supportive care (BSC) alone for patients with AGC (
This phase II study was designed to assess the activity and safety of the FOLFOX-4 regimen for previously treated patients with AGC. In our study, the response rate (RR) was 21% and the median OS was 6.2 months. These results are comparable with those reported by other phase II trials that have evaluated different FOLFOX regimens (
The most common toxicity in our study was neutropenia. Grade 3/4 neutropenia and febrile neutropenia developed in 40% and 7% of patients, respectively. However, in another phase II study using a different FOLFOX regimen, grade 3/4 neutropenia was observed only 15% of the patients (
Salvage chemotherapy is not appropriate for all patients. Therefore, the proper selection of patients who are likely to benefit from salvage chemotherapy is important. In our previous study with mitomycin C plus S-1 second-line chemotherapy (
In current study, we have shown that FOFOX-4 might be a modestly effective regimen with tolerable toxicities for the previously treated patients with AGC. Especially, this regimen can be considered a treatment option for those heavily-treated AGC patients with a good performance status.
Progression-free survival and overall survival.
Patient characteristics (n=42)
*Eastern Cooperative Oncology Group performance status, †Because the patients could have metastases at multiple sites, the total numbers of metastases are greater than the number of patients.
The prognostic factors by univariate anaylsis
*progression-free survival, †overall survival, ‡Eastern Cooperative Oncology Group performance status.
The multivariate analysis of the prognostic factors according to the Cox model
*confidence interval, †Eastern Cooperative Oncology Group performance status.
The worst toxicities in the evaluable patients (n=42)