Gastric cancer is the fourth most frequent malignancy and the second most common cause of cancer-associated mortality worldwide (1). This cancer is also the second most frequent malignancy in Korea (2). Although patients with early gastric cancer may be successfully treated by surgical resection, the majority of patients experience a relapse subsequent to the first surgical resection (3) or are initially diagnosed with unresectable, locally advanced or metastatic disease (4). For these patients with advanced or metastatic gastric cancer, the objective of treatment is to relieve symptoms, prevent tumor progression and prolong the survival time. Therefore, palliative chemotherapy may play an extremely important role in the treatment of advanced gastric cancer (AGC).

It has been reported that chemotherapy improves the survival of AGC patients in comparison to best supportive care, and it has also been reported that combination chemotherapy is superior to monotherapy in terms of survival, response rate and symptom control (5). In general, fluoropyrimidine, such as 5-fluorouracil (5-FU) or its oral prodrugs, and platinum, such as cisplatin or oxaliplatin, combination regimens are widely accepted as the standard first-line chemotherapy, with a response rate of 25–54% and a median overall survival time of 8–13 months (5–6). However, more than one-half of the patients with AGC that receive first-line chemotherapy do not demonstrate a response, and even in responders the duration of response may be as short as a few months (6). In addition, the number of patients that maintain a good general condition following the failure of first-line chemotherapy has increased due to the improvements in supportive care. As a result, the number of patients that are good candidates for subsequent salvage chemotherapy has increased. In previous years, novel drugs, including docetaxel, paclitaxel and irinotecan, have been tested in salvage chemotherapy for pre-treated AGC (7,8). With the availability of these active cytotoxic agents, numerous patients with refractory or relapsed gastric cancer subsequent to first-line chemotherapy have received salvage chemotherapy in routine clinical practice, particularly in Asia (8).

Although salvage chemotherapy following first-line treatment may be considered a confirmed option for the treatment of AGC, the impact of the availability of several active cytotoxic agents has not yet been assessed in AGC. Therefore, the present study assessed the impact of the availability of fluoropyrimidines, platinums, taxanes and irinotecan over the course of treatment on the survival of patients with AGC.

The present study retrospectively analyzed data obtained from 216 patients with AGC that had undergone palliative chemotherapy with active cytotoxic agents, such as fluoropyrimidines and platinums or taxanes or irinotecan. The present analysis demonstrated that the availability of these active cytotoxic agents in the course of treatment had a positive impact on the survival of patients with AGC. In the present study, 92 patients (42.6%) were treated with fluoropyrimidine and platinum only, while 75 patients (34.7%) received one more cytotoxic agent, irinotecan or a taxane, and 49 patients (22.7%) received all four active cytotoxic agents. Multivariate analysis revealed that the availability of more active cytotoxic drugs was an independent prognostic factor for survival compared with fluoropyrimidine and platinum only. This finding suggests that it is important to use all cytotoxic agents that have well-demonstrated clinical activity in AGC to guarantee the maximal benefit of systemic therapy for overall survival in patients with AGC.

Although the median survival time of patients with AGC remained below one year, numerous cytotoxic agents have been investigated over the previous decades, including fluoropyrimidines, which are administered orally or intravenously, anthracyclines, cisplatin, oxaliplatin, taxanes and irinotecan (5–7). Currently, various targeted agents are being tested in clinical trials and promising data have been recently published for trastuzumab-containing therapy, with median survival time exceeding one year (9). Novel oral fluoropyrimidines, including capecitabine and S-1, are not clinically inferior to 5-FU in terms of survival, and additional advantages of novel oral fluoropyrimidines include the convenience of oral chemotherapy, which avoids the potential morbidity associated with central venous access, and the opportunity to make simple dose adjustments to the oral agent during the treatment cycle to manage toxicity (10–13). Cisplatin has been an integral component of AGC reference regimens (6). However, oxaliplatin has been extensively studied in AGC due to the specific side-effects of cisplatin, including nephrotoxicity, emetogenicity and ototoxicity. Due to the non-inferior efficacy, oxaliplatin may be substituted for cisplatin in the treatment of AGC, and elderly patients may derive a particular benefit from treatment with oxaliplatin instead of cisplatin (10,14). Taxanes, such as docetaxel or paclitaxel, which bind and stabilize microtubules and therefore lead to cell-cycle arrest, have also been used as a first-line therapy for AGC (15,16). In addition, irinotecan has been reported to demonstrate activity in gastrointestinal cancers, and irinotecan-based combination regimens have been studied as a first-line alternative to platinum-based chemotherapy (17,18). The availability of these active cytotoxic agents opened the option of sequential salvage chemotherapy in AGC patients.

Second-line chemotherapy is currently considered to be a standard therapy option for patients that demonstrate disease progression during or subsequent to first-line chemotherapy. Docetaxel and irinotecan have been evaluated extensively for second-line therapy in patients for whom fluoropyrimidine and platinum have failed (19). Three randomized controlled trials have revealed the increased survival of patients administered with either docetaxel or irinotecan monotherapy compared with those receiving best supportive care (20–22). As the majority of patients with AGC are initially treated with fluoropyrimidine and platinum, it appears more prudent to avoid these drugs in second-line regimens for these patients. No statistically significant differences were observed between the overall survival, progression-free survival and response rates for patients receiving taxanes and those receiving irinotecan (19,23). Thus, either taxanes or irinotecan may be recommended as a treatment option for second-line chemotherapy in patients with AGC. Although evidence is limited with regard to the efficacy of third-line chemotherapy in AGC, this therapy may have contributed to the prolonged overall survival time. Several studies have demonstrated that third-line chemotherapy performs better compared with best supportive care in patients with AGC in terms of overall survival and quality of life (24–26). The sequence of second and third-line regimens, including taxanes and irinotecan, did not present any significant difference in overall survival or time to progression subsequent to the failure of fluoropyrimidine and platinum chemotherapy (24). The differences in toxicity profiles, previous chemotherapy agents, and treatment schedules between the two treatments may aid in choosing between taxanes or irinotecan.

The current results suggest that the use of all active cytotoxic agents improves the overall survival in patients with AGC. However, if sequential treatment with all active cytotoxic agents cannot be guaranteed for 100% of the patients, the use of a triplet combination protocol may be considered as first-line therapy. The safety and efficacy of this approach has been assessed in previous clinical trials (15,16). Triplet combination chemotherapy comprising an anthracycline or a taxane in addition to fluoropyrimidine and platinum compounds has resulted in higher response rates and a modest improvement in overall survival compared with doublet combinations (6). In the majority of European countries, the epirubicin, cisplatin and fluorouracil (ECF) regimen is more commonly used, based on a phase 3 randomized trial that compared the administration of the ECF regimen with the administration of fluorouracil, doxorubicin and methotrexate (27). The docetaxel, cisplatin and fluorouracil (DCF) regimen has previously been tested in the V325 phase 3 trial. In this trial, it was found that the DCF regimen not only significantly improved the clinical benefit of chemotherapy, but also improved the quality of life, time to progression and overall survival compared with cisplatin and fluorouracil without docetaxel (15). However, the high rate of treatment-associated toxicity limits the applicability of this regimen to all patients, particularly those that are elderly or have a poor performance status. Therefore, several modifications to the schedule of triplet combination chemotherapy or growth factor support have been investigated in an attempt to minimize the toxicity that occurs with this regimen (28,29).

Although the benefit of sequential salvage chemotherapy is evident, the disease control rate is 30–40%. This indicates that more than one-half of patients do not benefit from salvage chemotherapy and suffer from toxicities. Therefore, it is important to predict whether patients may benefit from sequential salvage chemotherapy. Previous studies have indicated that several factors should be considered in order to assess the response to sequential salvage chemotherapy, such as the performance status of the patient, extent of disease (locally advanced or metastatic), cumulative toxicity, lack of cross-resistance of the tumor cells to previously used drugs and progression-free survival of the patient following previous chemotherapy (26,30). Therefore, predictive factors for the potential survival benefit of salvage chemotherapy with active cytotoxic agents require additional investigation to avoid the development of toxic effects in patients that are unlikely to benefit from the therapy.

The present study demonstrates several limitations. Firstly, it is a retrospective analysis. However, all patients were consecutive non-selected cases that received chemotherapy treatment outside clinical trials and were followed by the Department of Internal Medicine, Chungbuk National University Hospital under the supervision of the same oncology team, which also addresses real-life situations. Secondly, a shorter overall survival time was demonstrated in the present study compared with previous studies. This is due to the population in the present study possessing a poor prognosis, with 97.7% of the patients experiencing metastatic cancer, 56.1% possessing peritoneal carcinomatosis and 9.3% demonstrating an ECOG performance status of 2–3.

In conclusion, the present study suggests that the availability of active cytotoxic agents in the course of treatment is associated with improved survival in patients with AGC. Additional prospective studies of effective administration schedules for patients receiving all active cytotoxic agents, in addition to studies investigating the factors that predict the survival benefit from salvage chemotherapy should continue in patients with AGC.