Patients with stage II or III gastric cancer are treated with surgical resection and perioperative chemotherapy. Platinum agents have established activity in this disease. Combination chemotherapy FLOT (5-fluorouracil, oxaliplatin, and docetaxel) is now standard perioperative treatment for resectable gastric cancer. 1 The study by Slagter and colleagues evaluated whether cisplatin was noninferior to oxaliplatin when used in the treatment of early-stage gastric cancer. Prior to the incorporation of FLOT into standard treatment practice, patients were treated with ECX (epirubicin, cisplatin, and docetaxel), as per the MAGIC trial .2 In the metastatic setting, chemotherapy regimens with either cisplatin or oxaliplatin as a choice of platinum agent have comparable activity against these tumors. Oxaliplatin activity has been shown to be noninferior to cisplatin in the randomized REAL2 trial in metastatic setting. 3
The study by Slagter and colleagues is a post hoc analysis of 781 patients with resectable gastric cancer who were enrolled in the CRITICS trial. This analysis demonstrated that chemotherapy regimens containing oxaliplatin and cisplatin had comparable 5-year overall survival rates. Not surprisingly, oxaliplatin was associated with higher neurotoxicity. Based on this analysis, it is likely safe to conclude that, just as in the advanced setting, cisplatin and oxaliplatin have similar activity in early-stage disease.
Mismatch repair protein deficient or microsatellite unstable gastric cancer (MSI-H) represent unique subtypes of gastric cancer, with distinct biologic behaviors and treatment responses. The efficacy of chemotherapy in patients with early-stage MSI-H tumors has been questioned previously. Similar to MSI-H colorectal cancers, the benefit of chemotherapy in resectable MSI-H gastric and esophagogastric junction tumors appears to be less robust than in microsatellite stable (MSS) tumors. In the exploratory analysis of patients with MSI-H tumors enrolled in the perioperative MAGIC trial, patients with MSI-H tumors had better prognosis when treated with surgery alone and potentially experienced detrimental effects from chemotherapy. 4 The retrospective analysis by Vos and colleagues adds to the body of knowledge about early-stage MSI-H gastric cancers. They evaluated 535 patients with early-stage disease who were treated with surgery alone or surgery plus perioperative therapy between 2000 and 2018. The overall survival in 82 patients with MSI-H tumors was 20% better than in those with MSS disease. This favorable outcome was seen irrespective of whether chemotherapy was given. Though these results suggest that chemotherapy may not be necessary in the treatment of these tumors and there are emerging data regarding the activity of immune checkpoint inhibitors in this setting, these results should definitely be investigated further in prospective studies. 5 However, in the absence of prospective randomized data, it is difficult to recommend deviating from the established standard of care with FLOT, especially for patients undergoing curative intent treatment.
A study by Yukami and colleagues evaluated whether the presence of liver metastasis, which have been shown to be enriched in immunosuppressive cells in the preclinical setting, had any bearing on the activity of immune checkpoint inhibitors alone or in combination with multi-tyrosine kinase inhibitors. The analysis included 54 patients enrolled in a phase 1b trial of REGONIVO (regorafenib and nivolumab) and a phase 2 trial of LENPEM (lenvatinib and pembrolizumab). With a median follow up of 14 months, there was no significant difference in the efficacy of the above regimens (overall survival, progression-free survival, and objective response rate) between patients with and without liver metastasis. The promising activity of these combinations is continuing with longer follow-up. The above regimens should be investigated further in larger prospective studies irrespective of metastatic sites.