Esophagus to Small Intestine
N Engl J Med. 2024;391(19):1810-1821
Preoperative chemoradiotherapy for resectable gastric cancer
Background: In Western countries, the current standard of care for resectable gastric cancer is perioperative chemotherapy. Preoperative chemoradiotherapy has been considered, but data are limited regarding this treatment as compared with perioperative chemotherapy alone.
Methods: The authors conducted an international, phase 3 trial in which patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive preoperative chemoradiotherapy plus perioperative chemotherapy or perioperative chemotherapy alone (control). In both groups, patients received either epirubicin, cisplatin, and fluorouracil or fluorouracil, leucovorin, oxaliplatin, and docetaxel both before and after surgery; the preoperative-chemoradiotherapy group also received chemoradiotherapy (45 Gy in 25 fractions of radiation, plus fluorouracil infusion). The primary end point was overall survival, and secondary end points included progression-free survival, pathological complete response, toxic effects, and quality of life.
Results: A total of 574 patients underwent randomization at 70 sites in Australasia, Canada, and Europe: 286 to the preoperative-chemoradiotherapy group and 288 to the perioperative-chemotherapy group. A higher percentage of patients in the preoperative-chemoradiotherapy group than in the perioperative-chemotherapy group had a pathological complete response (17% vs. 8%) and greater tumor downstaging after resection. At a median follow-up of 67 months, no significant between-group differences in overall survival or progression-free survival were noted. The median overall survival was 46 months with preoperative chemoradiotherapy and 49 months with perioperative chemotherapy (hazard ratio for death = 1.05; 95% confidence interval: 0.83–1.31), and the median progression-free survival was 31 months and 32 months, respectively. Treatment-related toxic effects were similar in the two groups.
Conclusions: The addition of preoperative chemoradiotherapy to perioperative chemotherapy did not improve overall survival as compared with perioperative chemotherapy alone among patients with resectable gastric and gastroesophageal junction adenocarcinoma.
Prof. Dr. Michael Quante
Head of Gastrointestinal Oncology, Department of Internal Medicine II, University Medical Center Freiburg (Germany)
Chemotherapy or Chemoradiotherapy? The Current State of Neoadjuvant Therapy of the Gastroesophageal Junction and Gastric Cancer
Standard neoadjuvant therapy for gastric cancer is based on perioperative chemotherapy, which reduces tumor volume, treats micrometastases, and improves the R0 resection rate. However, the role of radiotherapy (RT) in the neoadjuvant treatment of resectable adenocarcinomas of the stomach and gastroesophageal junction (GEJ) remains controversial.
For GEJ carcinomas, the combination of neoadjuvant chemoradiotherapy (NACRT), surgical resection, and adjuvant chemotherapy has traditionally been applied. Recent studies, however, have questioned this approach. The Neo-AEGIS trial demonstrated equivalence between preoperative chemotherapy with ECF (epirubicin, cisplatin, and 5-FU) and preoperative chemoradiotherapy with carboplatin/paclitaxel. Additionally, the ESOPEC study showed the superiority of perioperative FLOT therapy (5-FU, leucovorin, oxaliplatin, and docetaxel) to preoperative chemoradiotherapy with carboplatin/paclitaxel.
In the context of neoadjuvant therapy for gastric cancer, a meta-analysis of 7 randomized controlled trials (601 patients) comparing NACRT with NACT revealed significant advantages of NACRT: higher R0 resection rates, improved pathological complete response rates (pCR), and longer median survival – with comparable adverse effects and postoperative complications. These findings supported the notion that chemoradiotherapy plays an important role in the neoadjuvant treatment of gastric cancer.
The phase 3 TOPGEAR trial examined the benefit of NACRT in addition to perioperative chemotherapy compared to perioperative chemotherapy alone in 574 patients with resectable gastric (65%) or GEJ (35%) adenocarcinoma. Preoperative therapy consisted of either chemotherapy alone or a sequence of preoperative chemotherapy followed by chemoradiotherapy (4500 cGy with capecitabine or 5-FU). All patients received adjuvant chemotherapy after surgery. NACRT significantly increased the proportion of patients with pCR (17% vs. 8%) and tumor downstaging but did not lead to improved overall survival (46 months vs. 49 months; hazard ratio = 1.05; 95% confidence interval: 0.83–1.31) or progression-free survival (31 months vs. 32 months). Adverse effects and severe surgical complications (≥ grade 3) were comparable between the groups.
The results of the TOPGEAR trial indicate that adding radiotherapy to preoperative chemotherapy in resectable gastric and GEJ carcinomas does not provide a survival benefit. Combined with the findings of the Neo-AEGIS and ESOPEC trials, perioperative chemotherapy, particularly with FLOT, is recommended as the standard treatment. The use of chemoradiotherapy should be limited to patients who cannot undergo surgery. Future analyses may identify specific subgroups
that could benefit from NACRT. Advances in molecular tumor characterization, as well as in radiotherapy and surgical techniques, may also enable personalized approaches in the future.