Platinum-based drug used in combination with fluorouracil is recognized standard first-line chemotherapy for metastatic gastric cancer. S1 is a new oral drug of fluorouracil, combines tegafur with two modulators of gimeracil and oteracil , compared with capecitabine shows lower incidence of hand foot syndrome (HFS). S1 plus platinum has been demonstrated has favorable efficacy in Asia advanced gastric cancer patients. ORR and DCR of SOX were reported to be 32.6-58% and 75-85.2% respectively in first line randomized phase III studies. Median PFS and OS were 5.5-5.7 months and 12.9-14.1 months, respectively [4, 5, 7]. Especially for the non-intestinal Lauren’s type gastric cancer, SOX had a prolonged OS compared with SP in Chinese patients . Based on the excellent efficacy and acceptable toxicity [4, 5, 14, 15], SOX is one of the most common regimens for the first line chemotherapy of advanced gastric cancer in Asia. However, elderly gastric cancer patients usually in poor performance status and complicated with underlying disease such as hypertension, diabetes and coronary heart disease. Therefore, S1 monotherapy became a choice for the patients who could not tolerate 3-weekly combination chemotherapy. Nevertheless, the effect of S1 monotherapy in first line setting was limited. ORR was only 24.7-31%, and median OS was 10.5-10.8 months [16–18], inferior to the chemotherapy with fluoropyrimidine and platinum . In consequence, there is an urgent need to explore therapeutic options with satisfactory efficacy and acceptable tolerability for elderly patients of advanced gastric cancer.
This phase 2 study showed that biweekly SOX could bring out a promising survival as first-line therapy in Chinese elderly metastatic gastric cancer patients with a median age of 68 years old, preliminarily. Compared with S1 monotherapy, biweekly SOX had a tendency to improve the efficacy with higher ORR (54.2%) and DCR (85.7%). And the median PFS and OS of biweekly SOX was 4.6 months and 11.1 months, respectively, seemed to be similar with 3-weekly SOX. Furthermore, in another phase II study, the effect of biweekly SOX (oxaliplatin 85 mg/m2 d1, S1 80-120mg/day d1-7, every 2 weeks) in the first line treatment was evaluated. ORR and DCR were 30.43% and 76.08%, respectively . The patients with median age of 59 years old acquired a PFS of 4.4 months and OS of 10.3 months , who were much younger than our patients. In that study, 78.3% of patients accepted second line chemotherapy, whereas the proportion of our patients was 63.2%. In our study, 7 HER2 positive patients didn’t accept trastuzumab for financial reasons, might have a negative effect on the survival. Even so, our biweekly SOX in the elderly patients showed similar effect compared with the counterpart in the previous phase II study.
A series of clinical studies demonstrated that 3-weekly SOX (oxaliplatin 130 mg/m2 d1, S1 80-120mg/day d1-7, every 3 weeks) had accumulated significant hematological and neurological toxicity [6–9]. Therefore, the dose of oxaliplatin was reduced to 100mg/m2 every three weeks in G-SOX phase 3 study. However, the modified 3-weekly SOX didn’t show lower toxicity. Grade 3-4 neutropenia and thrombocytopenia were still reported to 19.5% and 10.1%. The rate of any grade peripheral neuropathy was up to 85.5%. As a result, 48.5% and 5% of the patients accepted dose reduction of oxaliplatin or treatment discontinuation in G-SOX phase 3 study, respectively . Advanced gastric cancer patients usually suffered from weight loss, malnutrition and chronic anemia which might impair the tolerance to anti-tumor therapy, especially for the elderly patients. In our study, about 1/4 of the patients were complicated with cardiovascular or cerebrovascular disease, with high-risk of acute attack of underlying diseases if suffering from severe TRAEs. This study demonstrated well tolerance of biweekly SOX by reducing single dose of oxaliplatin and shortening treatment course of S1 in these elderly patients. Any grade neutropenia was 57.1%, similar with the result reported by previous biweekly SOX phase 2 study (54.35%) , and lower compared with 3-weekly SOX phase 3 studies (65.6% and 68.9%) [4–5]. Only 2.4% patients developed grade 3 neutropenia, no grade 4 neutropenia occurred. There was no ≥ grade 3 thrombocytopenia observed in this study, while the incidence was up to 7.5-17% in 3-weekly SOX [4–9]. Furthermore, this biweekly SOX seemed to show better tolerance in peripheral neurotoxicity and digestive symptoms compared with 3-weekly SOX, any grade peripheral neuropathy, nausea and vomiting were less frequent (19% vs. 34-85.5%, 54.8% vs. 61.5-74.6% and 28.6% vs. 34.9ཞ59.9%) [4–9]. Most of these elderly patients could keep good physical conditions during treatment. As a result, biweekly SOX might bring a better quality of life in elderly advanced gastric cancer patients with lower toxicity.
Moreover, the patients with better nutritional and physical status seemed to have longer OS in this study. Compared with the ones with lower BMI, the patients of BMI≥18.5kg/m2 showed longer OS of 3.2-5.2 months numerically (p= 0.188). The OS of patients with ECOG 0 and 1 were 12.9 months and 10.6 months respectively (p= 0.719). Nutritional and physical status was closely correlated with immune function and treatment tolerance [20–21], which might compromise the treatment effect. Elderly patients were usually with lower level of albumin and lymphocyte, which was associated with poorer nutritional status and immune function [22–25]. Nutritional guidance and intervention during chemotherapy were revealed to lead an increase in the CD4+ lymphocyte and alleviate the hematological and digestive toxicity . Therefore, integration of nutritional supportive care into chemotherapy might be helpful to improve the tolerance and completion of anti-tumor treatment in elderly patients, subsequently prolonged the survival.
The limitation of this study was not randomized and had a small sample size undertaken in a single institution. Therefore, the anti-tumor activity results were preliminary, needing further accrual and evaluation.