1. This phase 3, randomized controlled trial demonstrated that S-1 plus oxaliplatin (SOX) was noninferior with respect to cancer-related outcomes versus fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as perioperative chemotherapy regimens for locally advanced gastric cancer

2. The SOX cohort demonstrated a non-statistically significant 7.4% increase in 3-year overall survival compared to the FOLFOX group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: The prognosis for advanced gastric cancer is poor. Perioperative chemotherapy has been demonstrated to improve survival for locally advanced resectable gastric cancer compared to surgery alone in multiple randomized controlled trials. S1 with oxaliplatin (SOX) is a chemotherapy regimen that has demonstrated a positive clinical response with limited side effects for unresectable gastric cancer. The FOCUS study, a phase 3, multi-centred, randomized controlled trial, compared clinical outcomes between SOX and fluorouracil, leucovorin, and oxaliplatin (FOLFOX) as perioperative chemotherapy regimens for locally advanced gastric cancer. Patients were randomly assigned to receive either perioperative SOX or FOLFOX as well as surgery. All data in this paragraph is written as patients who received SOX versus patients who received FOLFOX. Neutropenia was the most common grade 3 or 4 hematological adverse effect in both groups from chemotherapy. Local recurrence during the follow-up period occurred in 3.8% versus 2.5% of patients, and distant metastases occurred in 24.3% versus 23.6% of patients. There was no significant difference in the primary outcome of 3-year overall survival rates between groups with an absolute difference of 7.4% in favour of the SOX cohort. The 3-year progression-free survival was also similar between cohorts. Overall, the FOCUS trial demonstrated that SOX was non-inferior to FOLFOX as a perioperative chemotherapy regimen for locally advanced gastric cancer. This study had a long follow-up period of 8 years which can trend recurrence rates for an extended period; however, during this period, treatment for metastatic gastric cancer has improved, leading to higher survival rates.

Click to read the study in JAMA Network Open

Relevant Reading: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine

In-Depth [randomized controlled trial]: This trial enrolled 583 patients with gastric adenocarcinoma at the T4N stage with no metastasis from 12 Chinese hospitals between June 2011 and August 2016. Patients were randomized (1:1) to receive perioperative SOX (n= 293) or FOLFOX (n= 290). Chemotherapy was administered for 2-4 cycles preoperatively and 2-4 cycles postoperatively; surgery was completed within 2 weeks of the final preoperative chemotherapy cycle. The follow-up period was every 3-6 months for the first two years, every 6-12 months from years 3-5, followed by annually after five years. The primary outcome was overall survival (OS) which was death by any cause post-randomization. All data in this paragraph is written as patients who received SOX versus patients who received FOLFOX. Upon assessment of adverse events from chemotherapy, the incidence of neutropenia was 19.4% vs. 24.3%, and thrombocytopenia incidence was 11.1% vs. 2.8%. Regarding surgical outcomes, no significant differences were found concerning dissected lymph nodes and postoperative morbidity. Median follow-up was 61 (2-96) months vs. 60 (1-96) months. Death occurred in 30.9% of patients in the SOX cohort compared to 35.0% of patients in the FOLFOX cohort, resulting in 3-year OS rates of 75.2% (95% CI: 70.3-80.5) and 67.8% (95% CI: 62.5-73.5) (hazard ratio: 0.84 [95% CI: 0.63-1.13). Furthermore progression-free survival was 69.3% (95% CI: 64.0-74.9) vs. 64.5% (95% CI: 59.1-70.4) with a hazard ratio of 0.95 (95% CI: 0.72-1.25).

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