Abstract
Background: The Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC) demonstrated that S-1(TS-1, an oral fluoropyrimidine) was effective as adjuvant chemotherapy for patients with pathological stage II or III gastric cancer who underwent curative gastrectomy. The objective of this study was to clarify the risk factors for recurrence in patients who received S-1 adjuvant chemotherapy. Patients and Methods: We retrospectively analyzed the factors predicting recurrence in 77 patients with stage II or III gastric cancer who received S-1 chemotherapy following R0 gastrectomy between April 2003 and October 2008. Results: The tumor diameter, macroscopic appearance, and presence of lymph node metastasis were significant factors predictive of recurrence identified by the univariate analysis. Moreover, the tumor diameter was an independent risk factor identified by the multivariate analysis. Conclusion: It is necessary to establish a chemotherapeutic regimen for patients with stage II/III gastric cancers with large tumor diameter.
Gastric cancer remains one of the leading causes of cancer-related deaths. It is the second leading cause of mortality worldwide, and the second most common cause of cancer-related deaths following lung cancer in Japan (1).
Many clinical studies have been carried out in an attempt to improve the prognosis after surgery. Oral S-1 (TS-1) monotherapy has been reported to improve the survival of patients with stage II/III gastric cancer who underwent a curative gastrectomy with D2 lymph node dissection based on the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer [ACTS-GC (2)], and this has become a standard treatment in Japan.
However, approximately 30% of these patients still develop recurrences even after adjuvant S-1 therapy (2). The prognosis of these patients was poor even when they received chemotherapy after recurrence (3). It is important to identify patients at an increased risk of recurrence after curative resection followed by S-1 adjuvant chemotherapy, because these patients should be treated with an alternative adjuvant regimen other than S-1. We therefore investigated the prognostic factors for recurrence in such patients.
Patients and Methods
Patients. Patients fulfilling the following eligibility criteria were selected from a prospective database established at the Yokohama City University Medical Center: histologically-proven gastric adenocarcinoma; R0 resection with D2 and D1 or more radial lymph node dissection during 2003-2008; pathological stage II or III, according to the UICC-TNM seventh edition (4); received adjuvant S-1 chemotherapy after surgery; received no previous treatment for cancer except for initial gastric resection for the primary lesion.
For the surveillance of tumor recurrence, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) tumor marker levels were checked at least every three months for five years. Multidetector-row computed tomography (MDCT) scanning with a slice thickness of 5 mm was performed every three months during the first three years after surgery, and then every six months until five years after surgery. Patients received S-1 administration until one year after gastrectomy if there was no evidence of tumor recurrence or unacceptable toxicity. The initial dose was 80 mg/m2 for four weeks, followed by treatment at two-week intervals, according to the ACTS-GC protocol. Principally, we followed this protocol, but the treatment schedule was modified at the physician's discretion according to each patient's toxicity profile. If a patient had hematological toxicity ≥grade 3 or non-hematological toxicity ≥grade 2, their protocol was changed, such as administration for two weeks, followed by a one-week rest interval. If this three-week cycle protocol was not tolerable, the patient's daily dose was reduced from 120 mg/ body to 100 mg/ body, or from 100 mg/ body to 80 mg/ body. We discontinued S-1 therapy for cases with unacceptable adverse effects in spite of these methods, or at the patient's request. Adverse events were assessed according to the Common Toxicity Criteria of National Cancer Institute (version 4.0) (5).
Statistical analysis. Comparison of proportions of patients was evaluated by a chi-square test. The recurrence-free survival (RFS) was calculated by the Kaplan–Meier method and was then compared by the log-rank test. A multivariate RFS analysis was performed using a Cox proportional hazards model and a logistic regression analysis. The accepted level of significance was p<0.05. Variables associated with survival (p<0.10) in the univariate analysis were included in the multivariate analysis using the reducing variables methods. The SPSS software package (v17.0J Win; SPSS, Chicago, IL, USA) was used for all statistical analyses.
Results
Short-term results. Seventy-seven patients (50 males), with a median age of 65.5 (range=42-80) years, were included in this study. Partial gastrectomy was performed in 38 patients, and total gastrectomy was performed in 39 patients. Laparoscopic surgery was carried out in two patients, and blood transfusion was performed for two patients. In 10 patients (12.9%), postoperative complications were recorded, and the mean length of hospital stay was 10.6±12.5 days. The pathological stage was classified as IIA in 11 patients, IIB in 18, IIIA in 14, IIIB in 12, and IIIC in 22 patients. Twenty-three (29.9%) patients developed disease recurrence. Among these patients, the primary site of the recurrence was the peritoneum in 11 patients (47.8%), lymph nodes in seven patients, and the liver in seven patients (30.4%), respectively. The median survival time (MST) for patients overall was 72.7 months (range=4.3-90.2 months; Figure 1A). The median RFS was 28.8 months (range=3.1-49.4 months), and the median survival time after recurrence was 13.3 months (range=1.6-21.7 months). The prognosis was significantly poorer in patients with recurrence (MST=32.9 months) compared to patients without recurrence (MST=87.5 months, p<0.001, Figure 1B).
Duration of adjuvant S-1 therapy. The median duration of taking S-1 treatment was 12 months. Most patients were able to receive the full-planned treatment with adjuvant chemotherapy, but 33 patients (42.7%) discontinued S-1. The mean duration of treatment was 8.6 months, so we divided the patients into two groups at nine months in order to analyze the association between the duration of treatment and recurrence.
The causes of withdrawal of treatment are listed in Table I. The reasons for withdrawal of treatment were adverse events in 23 patients (69.6%), and refusal in nine patients (27.2%). Adverse events consisted of anorexia in nine patients and general fatigue in six patients. One patient discontinued S-1 because of disease recurrence.
Comparison of clinicopathological factors according to recurrence. The correlations between the rate of recurrence and the clinicopathological factors are shown in Table II. Age was divided into two groups by the median age.
A tumor size larger than 5 cm was a risk factor for recurrence (p=0.003). In addition, the macroscopic appearance and presence of lymph node metastasis also affected the recurrence rate. There were no significant differences in other factors, including the histological type and the depth of invasion.
Factors prognostic of recurrence. The RFS for each clinical factor is provided in Table III. In the univariate analysis for RFS, it was demonstrated that macroscopic tumor size, and macroscopic type were significant predictive factors. Finally, the macroscopic tumor size was selected as an independent predictive factor for recurrence by multivariate analysis. Multivariate logistic regression analysis also supported this finding (Table IV). Time-to-recurrence was significant in two groups (Figure 2).
Discussion
In this study, we revealed that a tumor diameter of 5 cm or more was an independent predictive factor for recurrence of gastric cancer after adjuvant S-1 therapy. We also previously reported that the tumor diameter was a prognostic factor in patients with gastric cancer (6), and many reports support these data (7, 8). However, few studies have focused on the factors predictive of recurrence and prognostic factors after adjuvant S-1 chemotherapy for stage II/III gastric cancer.
One previous study reported that the macroscopic tumor diameter was an independent prognostic factor for stage II/III gastric cancer in patients who underwent curative resection following S-1 administration (9). However, this study discussed overall survival, then it was unclear whether the tumor diameter was also a risk factor for recurrence or related to poor prognosis after recurrence. In another report, the tumor diameter and lymph node metastasis were identified as risk factors for peritoneal recurrence in spite of S-1 adjuvant chemotherapy (10). Our current study clearly demonstrates that the tumor diameter was an independent factor predictive of recurrence in patients with curatively-resected stage II/III gastric cancer who received adjuvant chemotherapy with S-1. To our knowledge, this is the first study which has focused on any kind of recurrence in patients who received S-1 adjuvant chemotherapy, and revealed that it is necessary to perform intensive adjuvant chemotherapy for patients with large tumors. The results of the SPIRITS study (S-1 vs. S-1 plus cisplatin) established the superiority of the S-1 plus cisplatin combination therapy over S-1 monotherapy for metastatic and recurrent gastric cancer (11), hence S-1 plus cisplatin may be promising as adjuvant chemotherapy for patients with stage II/III tumors measuring 5 cm or larger in diameter.
Recently, pT, pN, and the histological type were reported as prognostic factors in patients with gastric cancer (12). In this study, the tumor diameter was a stronger predictive factor for recurrence compared to these factors. This study focused on patients with stage II or III tumors, which might have reduced the influence of the pathological T and N stages on recurrence, hence only the tumor diameter was identified as an independent predictive factor. Another report suggested that tumor diameter is an independent prognostic factor, and especially in patients with large tumor, the depth of invasion was selected as an independent prognostic factor (6). Larger tumors are frequently undifferentiated, invade the serosal surface, and preferentially cause peritoneal recurrence. In this study, tumor size was not correlated with the pattern of recurrence (data is not shown), but this may have been a result of the sample size.
Another study reported that administration of S-1 for more than one year after the operation improved the RFS (13). The present study demonstrated that the recurrence rate of patients who received S-1 for less than nine months tended to be slightly higher than that of those who received S-1 for more than nine months, although the length of administration of S-1 was not selected as an independent predictive factor by the multivariate analysis. The duration of treatment often depends on factors such as a poor performance status or preoperative complications, and so these patients often cannot receive another chemotherapeutic regimen after disease recurrence. Therefore, it is difficult to conclude whether the shorter duration of S-1 administration was related to recurrence.
This retrospective study has several limitations. Firstly, the cut-off for the tumor diameter may not be optimal. It is necessary to establish an acceptable definition for ‘large tumor diameter’. Secondly, the number of patients was relatively small in this study.
Greater tumor diameter was found to be an independent prognostic factor for recurrence in patients with curatively resected stage II/III gastric cancer who subsequently received S-1. It is necessary to establish an optimal chemotherapeutic regimen for these patients in order to help prevent recurrence and improve their prognosis if recurrent disease develops.
- Received February 22, 2013.
- Revision received March 19, 2013.
- Accepted March 20, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved