Abstract

INTRODUCTION

Gastric cancer is the fourth most common malignant disease and the second leading cause of cancer-related death worldwide.[1] In East Asian countries, the screening for gastric cancer is routine due to the highest rates of incidence.[2] The treatment of gastric cancer is optimized by the fine combination of surgery, radiotherapy, chemotherapy, and molecularly targeted medicines. Surgery represents the foremost intervention for curable gastric cancer and the extent of lymph node dissection is an important variable, which shows significant distinctions worldwide. In East Asia D2 dissection has been routinely performed since the 1960s,[3] while in most of the Western countries D1 dissection is preferred. Two prospective randomized trials performed in the Netherland and the UK[4,5] showed that D1 dissection was associated with less mortality and morbidity compared to D2 dissection. However, some issues were identified in these trials such as an inadequate D2 dissection and common execution of distal pancreatectomy and splenectomy, which is currently considered unneeded.[6] Moreover, a 15 years follow-up of the Dutch D1D2 trial, showed that D2 lymphadenectomy is associated with lower loco-regional recurrence and gastric-cancer-related death rates than D1 surgery.[7] Recent studies have demonstrated that D2 gastrectomy could produce benefits in Western patients when conducted in experienced Western centers[8,9,10] and currently in Europe spleen preserving D2 resection is recommended and available in high-volume centers. On the other hand, in Japan, a clinical trial comparing D1 versus D2 would be considered inappropriate today. Partly depending on this discrepancy in the surgical modalities, the complementary chemotherapeutic and radiation treatments for gastric cancer are not applied homogeneously in the different geographical areas. In Europe, perioperative chemotherapy with epirubicine, cisplatin and infusion fluorouracil (ECF) without radiation is frequently used in gastric cancer patients based on the results of a phase III trial, which showed how this approach signifi cantly improves progression-free and overall survival (OS).[11] In the USA, postoperative radiochemotherapy was evaluated by conducting a phase III trial in patients with gastric cancer which underwent R0 resection, demonstrating an improvement of recurrence-free survival, and OS in 10 years follow-up.[12] In Japan, adjuvant therapy with S-1 for 1-year is a standard of care after it showed effectiveness in all subgroups of patients who underwent D2 resection in a phase III study.[13] Investigators in China and Korea conducted a phase III trial showing that postoperative therapy with capecitabine/oxaliplatin improves both disease-free survival (DFS) and OS with respect to surgery alone in patients, which underwent D2 resection for stage IIA-IIIB gastric cancer.[14] In the locally advanced and metastatic gastric cancer, systemic chemotherapy based on platinum-fluoropyrimidine combinations is the standard of care almost everywhere in the world. New molecular versions of these drugs, such as oral fluoropyrimidines and oxaliplatin, have already shown noninferiority while decreasing toxicity.[15] At the failure of the first line chemotherapy, other agents such as taxanes and irinotecan, can improve survival.[16,17] Targeted therapies are acquiring an important part in advanced gastric cancer (AGC) treatment, such as the addition of trastuzumab to the fluoropyrimidine-platinum combination in first line for HER-2 positive patients[18] or the anti-angiogenic monoclonal antibody ramucirumab beyond first line as a single agent and in combination with Paclitaxel.[19,20] Asian studies report better gastric cancer survivals compared to Western ones[11,13,21,22] and a recent retrospective investigation conducted on Asian and non-Asian individuals in the USA by controlling for the imbalance of known prognostic and treatment factors, found that the survival advantage of the Asian population continued to be present.[23] Due to this facts, in this paper we are going to highlight once more the East-West differences in the surgical approach and chemotherapy by focusing, eventually, on the role of the systemic treatment with the new oral fluoropyrimidine S-1, which has showed contrasting clinical benefit rates and toxicity profiles in these two different areas. Our conjecture is that the factors, which determine the divergent outcomes in these different population can be divided into changeable and unchangeable elements. We will try to identify some of these factors by reviewing trials of gastric cancer treated with S-1 conducted separately on Asian and Caucasian populations and eventually extrapolate data that could suggest the different “causality proportion” of the changeable versus the unchangeable elements in bringing the different outcomes in the S-1 treatment.

ORAL FLUOROPYRIMIDINES AND S-1

Fluoropyrimidines are emblematic of a rational anti-cancer drug design and 5-fluorouracil (5-FU) has become the most widely used among them since it was first introduced in 1957.[24] In Figure 1 are summarized the metabolic pathways and action mechanisms of 5-FU. Only 1-3% of the original dose of 5-FU will engage in the intracellular anabolic pathways[25] that generate its effective cytotoxic metabolites. The central factor in 5-FU catabolism is dihydropyrimidine dehydrogenase (DPD), an enzyme expressed mostly in the liver cells but also in intestine mucosa and various other tissues. 5-FU is catabolized by DPD finally leading to the formation α-fluoro-β-alanine [Figure 1] which is the main responsible for the toxicity related to 5-FU.[26,27] Early clinical use of 5-FU relied on simple intravenous (i.v.) administration in bolus until the superiority of i.v. continuous infusion was demonstrated in terms of response rate (RR), OS, and toxicity.[28] However, this led to the inconvenience of pumps and implantable catheters; consequently, the oral administration of 5-FU was assessed having as a rationale the potentiality to approximate or even improve the pharmacokinetics of continuous infusion. The oral prodrugs of 5-FU have been developed by refashioning biochemically the molecule into compounds which are not substrates for DPD and are, therefore, absorbed intact through the gastrointestinal (GI) mucosa needing to be activated subsequently into 5-FU by enzymes. The first three prodrugs which signed the passage to oral formulations are represented by carmofur, doxifluridine, and tegafur (ftorafur) [Figure 2]. Ftorafur (tegafur; R,S-1-1 (tetrahydrofuran-2-yl)-5-FU) is the main ancestor of S-1, the novel oral fluoropyrimidine we are going to focus on in our paper, but it has a limited clinical use on its own due to the important neurological and GI toxicities.[29] The combination of oral fluoropyrimidines, in the form of prodrugs, with agents which exert a targeted inhibition of DPD determines a prolongation of 5-FU half-life in plasma, a possible circumvention of 5-FU resistance due to DPD overexpression by cancer cells,[30] a better oral absorption, an increased sensitivity to the drug as well as the elimination of some toxic metabolites.[31] The application of a second modulation to the 5-FU prodrug/DPD inhibitor [Figure 2] finally brought to S-1, a combination of tegafur and two 5-FU modulators, gimeracil (5-chloro-2,4-dihydroxypyridine [CDHP]), and oteracil (oxonate), in a molar ratio of 1:0.4:1 [Figure 2], that enhances the anticancer activity and reduces the GI toxicity of 5-FU (C14). Orally-administrable tegafur was developed as a drug which showed an excellent absorbability, a slight conversion to 5-FU in the GI tract and a gradual conversion to 5-FU by cytochrome p450 enzymes in the hepatocytes.[32,33] Subsequently, CDHP was reported as one of the strongest inhibitors of DPD[34] and some further studies investigated the possibility of decreasing the GI toxicity of 5-FU without decreasing its antitumor activity by concomitant administration of a new molecule called oxonate, which localizes in GI mucosa and selectively inhibits the orotate phosphoribosyltransferase (OPRT), limiting 5-FU phosphorylation to FUMP, therefore reducing GI toxicity effects.[35] Based on these conclusions, tegafur and CDHP were given per OS concurrently to sarcoma-bearing rats at different molar ratios, and then oxonate was given orally during the consecutive administration of the tegafur-CDHP mixture and the final proposed formulation, called S-1, consisting of tegafur, CDHP, and oxonate at a 1:0.4:1 ratio, showed antitumor selective activity.[36] According to the findings of a Japanese phase I study, the recommended dose and administration for phase II trials were determined as twice daily administration of 75 mg/body for 28 consecutive days with 14 days rest (1 course).[37] Due to the significant differences between Asian and Caucasian patients in terms of Tegafur metabolism, phase I studies comprising only Western patients established lower recommended dose for S-1 (50-60 mg/m2/day for 4 weeks every 5 weeks).[38,39] Phase II studies have reported high RRs (35-50%) in different advanced solid tumors (gastric, colorectal, breast, and head and neck tumors).[40,41,42] In Table 1 we listed all the oral fluoropyrimidine compounds assessed in the clinical setting.