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Clinical Edge Journal Scan Commentary: Gastric Cancer, May 2022

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Patients with advanced human epidermal growth factor receptor 2 (HER2)–negative gastroesophageal adenocarcinoma have poor prognosis, with overall survival of less than 1.5 years even in the most recent studies. 1Efforts are ongoing to improve the outcomes for these patients. Chemotherapy continues to play a critical role in the management of this disease. First-line triplet chemotherapy regimens have demonstrated superior activity in prior studies, but their use has been limited by associated toxicities. 2 At present, fluoropyrimidine and platinum doublet is a standard chemotherapy backbone for advanced disease. Taxanes also have an established role in the management of gastric cancer in both early lines (as part of perioperative neoadjuvant chemotherapy with docetaxel, oxaliplatin, fluorouracil, and leucovorin [FLOT regimen]) and advanced settings (primarily in combination with ramucirumab after progression on first-line chemotherapy). 3,4 The phase 3 LEGA trial by Rosati and colleagues evaluated the activity of fractionated docetaxel, oxaliplatin, and capecitabine vs epirubicin, oxaliplatin, and capecitabine in patients with advanced gastric cancer. The primary endpoint of this study was progression-free survival. It is important to note that it is well established that epirubicin has no significant activity in this disease and is not included in National Comprehensive Cancer Network (NCCN) guidelines for gastroesophageal adenocarcinoma. 5 Hence, this is ultimately a study comparing triplet vs doublet chemotherapy. There was no difference in progression-free survival and overall survival between the two arms. At first glance, it appears that docetaxel did not add to antitumor activity here. However, it is imperative to look at the chemotherapy doses in this study. The oxaliplatin dose of 80 mg/m 2 every 21 days was much lower than the 130 mg/m 2 every 21 days in the control arm and lower than in other standard regimens, such as FLOT and leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (FOLFOX) regimens where oxaliplatin is administered at a similar dose but on an every-14-day schedule. Dose intensity matters, and other triplet regimens, such as leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin (FOLFIRINOX), are worth investigating further on the basis of phase 2 efficacy and manageable toxicity profile. 6 For now, though, FOLFOX and capecitabine and oxaliplatin (CAPOX) remain standard chemotherapy backbones in the first-line setting.

In early-stage disease, perioperative chemotherapy plays a critical role. The triple-chemotherapy FLOT regimen is now the standard treatment in patients who are able to tolerate it. However, it is associated with significant toxicities, and modifications frequently are needed. In clinical practice, FOLFOX chemotherapy can be used in patients who are not candidates for FLOT. A phase 2 OGSG 1601 study enrolled 37 patients with clinical stage T3/T4a N1-3 M0 gastric cancer who received perioperative doublet chemotherapy with capecitabine and oxaliplatin. At the 3-year follow-up, this study continues to demonstrate good activity of this doublet chemotherapy, with an overall survival rate of 83.8% at 3 years and relapse-free rate of 73%. These results support the use of this doublet in patients who cannot tolerate a more intense chemotherapy regimen. The interpretation of this study is limited by its small size and nonrandomized design. Given what we know about the activity of this regimen in advanced disease, however, these results add to the body of evidence that supports the use of this doublet in select patients.

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