AIM: To evaluate the effects and safety of combination chemotherapy with oxaliplatin (L-OHP) and S-1 (SOX regimen) in older patients with advanced gastric cardiac adenocarcinoma (GCA).

METHODS: Seventy patients with advanced GCA were classified according to age into an older group (≥ 75 years) and a control group (< 75 years). The SOX regimen was administered to the two groups as follows: S-1 (40 mg/m² po bid) on days 1 to 14 followed by a 7-d off period, plus L-OHP (65 mg/m² iv) for 2 h on days 1 and 8 of a 21-d cycle. This regimen was repeated for four to six cycles. Response and swallow statuses were evaluated after two cycles (6 wk). Effects and toxicity were evaluated four weeks after chemotherapy was completed.

RESULTS: The response rate was 65.6% (21/32) in the older group and 68.4% (26/38) in the control group (χ² = 0.062 and P = 0.804). Improvement in swallowing was 78.1% (25/32) in the older group and 76.3% (29/38) in the control group (χ² = 0.032 and P = 0.857). Efficacy was 68.8% (22/32) in the older group and 65.8% (25/38) in the control group (χ² = 0.069 and P = 0.793). Toxicities were reversible and similar in both groups (P > 0.05).

CONCLUSION: The SOX regimen is an effective, safe and well-tolerated regimen for older patients with advanced GCA.

With constant improvement in the quality of life in modern society, people’s life span has been prolonged. However, the incidence of elderly patients with gastric cardiac adenocarcinoma (GCA) is gradually increasing, and the majority of these patients have advanced disease when they are diagnosed. Thus, these patients have few opportunities for surgery[1]. The only available treatment choice for advanced GCA patients is systemic chemotherapy[2-4]. Although chemotherapy for advanced gastrointestinal cancer has been proven to be superior to best supportive care (BSC) in terms of survival and quality of life[5-7], there has been evidence supporting more serious adverse events observed among older patients than younger patients[8]. For these reasons, most older patients with metastasis are usually offered BSC and not chemotherapy[9]. However, patients who are 75 years old can still have a considerable number of years to survive (perhaps more than 10 years)[10]. Therefore, it is important to find a highly effective and minimally toxic chemotherapy regimen for elderly patients with advanced GCA.

In the last decade, 5-fluorouracil (5-FU) has been considered a cornerstone of therapy for advanced gastrointestinal cancer. Therefore, combining 5-FU with oxaliplatin (L-OHP) is logical because there is considerable evidence of preclinical synergy between the two agents[11]. S-1 is an orally active prodrug of 5-FU which is a fourth generation oral fluoropyrimidine[12]. Recent clinical studies have reported that S-1 in combination with L-OHP has a high response rate ranging from 53% to 59% and an excellent toxicity profile in the treatment of advanced gastric cancer[13-15]. In these studies, however, there were only a few patients of 75 years of age or older. Furthermore, few studies on the outcome of the S-1 and oxaliplatin (SOX) regimen in patients with GCA have been reported. Therefore, we designed this study to determine the response rate and toxicity profile of SOX regimen in GCA patients over the age of 75 years.

The health of the elderly varies from the health of younger patients. Older people are prone to having multiple organ dysfunctions, lower immunity, lower resistance to disease, and lower resistance to senile diseases, leading to reduced tolerance to chemotherapy and increased sensitivity to side effects of these drugs. Generally, caution is required when administering chemotherapy to older patients because they may not be able to tolerate a routine dose or may experience serious side effects. However, a suboptimal dose may not achieve the desired therapeutic effect. Therefore, many experts avoid treating elderly patients with chemotherapy[20].

There is evidence[9,21], however, that older patients with advanced gastroesophageal carcinoma may benefit from chemotherapy. Tougeron et al[9] reported that palliative treatment is superior to BSC (6.7 ± 2.1 mo vs 1.8 ± 0.4 mo) in older patients (> 70 years of age) with advanced esophageal cancer. The effect of S-1 and cisplatin combination therapy in an 80-year-old patient with gastric carcinoma has been reported in a case study, and the histopathological examination of this patient revealed CR of the disease with no cancer cells[21]. Nevertheless, data regarding GCA is limited.

In this study, the SOX program was used to treat elderly people with advanced GCA to achieve the following goals: (1) to enhance the efficacy of treatment by using a new drug; (2) to reduce toxicity and improve tolerance; and (3) to create an opportunity for treatment in elderly patients with poor health.

S-1 is an effective derivative that combines tegafur with the following two modulators of 5-FU metabolism in a 1:0.4:1 molar ratio: 5-chloro-2,4-dihydroxypyridine (CDHP), a reversible inhibitor of dihydropyrimidine dehydrogenase (DPD), and potassium oxonate[12]. Tegafur, an oral prodrug of 5-FU, is gradually converted to 5-FU and is rapidly metabolized by DPD in the liver. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) of 5-FU in plasma during S-1 treatment have been found to be higher than the steady state concentration and AUC of 5-FU in plasma during protracted intravenous infusion of 5-FU at a dose of 250 mg/m² per day[22]. Potassium oxonate is an orotate phosphoribosyl transferase inhibitor, which is primarily distributed to the gastrointestinal tract. This component of S-1 decreases incorporation of 5-fluorouridine triphosphate into RNA in the gastrointestinal mucosa, and it reduces the incidence of diarrhea. F-b-alanine (FBAL) is the main metabolite of 5-FU. FBAL and fluorocitrate are thought to cause the neurotoxic and cardiotoxic effects of 5-FU by inhibiting the tricarboxylic acid cycle[22]. The CDHP component of S-1 inhibits DPD, which is the rate-limiting enzyme in the catabolic pathway of 5-FU. Consequently, the plasma FBAL concentration after oral administration of S-1 is significantly lower than the concentration after continuous infusion of 5-FU[12]. Therefore, the use of S-1 may decrease the incidence of neurotoxicity and cardiotoxicity. Ajani et al[23] reported significant safety advantages in the S-1/cisplatin treatment as compared with the infusional fluorouracil/cisplatin treatment for advanced gastric or gastroesophageal adenocarcinoma. They reported the following frequencies resulting from the two treatments: grade 3/4 neutropenia (32.3% and 63.6%, respectively), stomatitis (1.3% and 13.6%, respectively), and hypokalemia (3.6% and 10.8%, respectively).

L-OHP[24-25] is a third generation platinum anticancer drug developed to improve tolerability and ease of administration when compared to cisplatin. The rate at which L-OHP combines with DNA in the body is more than 10 times faster than cisplatin. L-OHP adheres more strongly to DNA, and it has a stronger cytotoxic effect than cisplatin and carboplatin. In addition, the unique diaminocyclohexane group in oxaliplatin avoids some of the resistance mechanisms developed against cisplatin, such as the mismatch repair defect and bypass replication mechanism. A phase III trial[26] for metastatic gastroesophageal adenocarcinoma has been conducted, with a treatment of fluorouracil and leucovorin combined with either oxaliplatin [fluorouracil, leucovorin and oxaliplatin (FLO)] or cisplatin [fluorouracil, leucovorin and cisplatin (FLP)] every two weeks. The results of this trial demonstrated that serious adverse events associated with FLO are significantly less than the events associated with FLP (9% and 19%, respectively) and that the median progression-free survival (PFS) improves with FLO when compared to FLP (5.8 mo and 3.9 mo, respectively). This trial also demonstrated that treatment with FLO results in significantly superior response rates (41.3% and 16.7%, respectively), improved median PFS (6.0 mo and 3.1 mo, respectively) and improved overall survival (13.9 mo and 7.2 mo, respectively) when compared to treatment with FLP in patients older than 65 years.

Studies have shown that L-OHP and S-1 are highly active against cancer and that they have a favorable toxicity profile. Furthermore, studies have also shown that L-OHP and S-1 are expected to replace cisplatin and fluorouracil, respectively, as a first-line treatment for advanced gastric cancer[13-15]. Moreover, the SOX program may be considered for treatment of older people because of the greater efficacy and low toxicity of this regimen when compared to cisplatin and fluorouracil.

The SOX regimen in this study resulted in no significant differences between the older and control groups with regard to chemotherapy sensitivity (65.6% and 68.4%, respectively, P = 0.804), symptom improvement (78.1% and 76.3%, respectively, P = 0.857), and short-term therapeutic effects (68.8% and 65.8%, respectively, P = 0.793). More severe side effects caused by the SOX regimen were not detected among the elderly patients when compared to the younger patients, and these side effects did not have a significant effect on treatment administration or quality of life. Therefore, these results suggest that there are treatment options available for elderly patients with cardia obstruction who cannot eat and that there is still an opportunity for these patients to survive if they can get adequate nutrition through nasal feeds.

In summary, the SOX regimen for advanced GCA has high efficacy and mild toxicity, and it can increase the survival and life span of patients with GCA. Moreover, the SOX regimen is a safe chemotherapy program for elderly patients in poor health. Therefore, it is not necessary to entirely avoid chemotherapy in elderly patients with advanced GCA because of their age. Instead, treatment recommendations should consider physiological age and standard KPS score. It is also reasonable to initiate chemotherapy if the patient can obtain sufficient nutrition (e.g., through nasal feeding). However, chemotherapy should not be administered to patients with KPS scores less than 60 points.

In this study, the therapeutic effects of the SOX regimen in both groups were higher than those reported in previous studies of patients with gastric cancer[13-15], which may have been due to the fact that this combination therapy was the first time any of the patients in this study were treated with chemotherapy, resulting in a higher sensitivity and minimal resistance to treatment. Other studies have included patients who had relapsed or failed treatment. Moreover, most of the patients in this study were classified as having stage IIIb GCA with only locally advanced cancer. In this study, there were only a few extensive cases of metastasized cancer. Additionally, the SOX program may be more effective at treating GCA than other types of gastric cancer.