Updates in version 2.2018 of the NCCN guidelines for gastric cancer
Authors: Huang Liu 
Published: June 2023

Comment
Preferred Regimen provides by expert group is adjusted: (1) Fluorouracil and cisplatin was no longer the Preferred Regimen for Preoperative Chemoradiation and Perioperative Chemotherapy (recommended as the other regimens); (2) Pembrolizumab (For second-line or subsequent therapy for MSI-H or dMMR tumors) was recommended as the Preferred Regimen for Second-Line or Subsequent Therapy; (3) Ramucirumab for adenocarcinoma (category 1 for EGJ adenocarcinoma; category 2A for esophageal adenocarcinoma) was no longer the Preferred Regimen for Second-Line or Subsequent Therapy. The NCCN guidelines recommend that PET/CT is used for preoperative staging due to its greater accuracy than either PET or CT alone. It helps identify M1 patients, distinguish local lesions in the early course from those in the late course of the disease, and screen appropriate candidates for surgical treatments. However, preoperative PET/CT assessment for gastric cancer has a long way to go before it can be routinely performed in our country because CT assessment remains the first choice in most cases. Nevertheless, PET/CT is worth recommending to patients with difficult staging situations. The indications for neoadjuvant treatment are still highly controversial among Eastern and Western countries. A common status quo in our country is that more aggressive surgeries are performed with a low proportion of cases receiving preoperative radiochemotherapy. Phase III MAGIC trial, compared perioperative chemotherapy with epirubicin, cisplatin, and fluorouracil (ECF) to surgery alone, established that perioperative chemotherapy improved OS and PFS in patients with non-metastatic stage II and higher gastric and EGJ adenocarcinoma. In the FNCLCC ACCORD 07 trial (n = 224 patients; 25% had gastric adenocarcinoma), Ychou et al reported that perioperative chemotherapy with fluorouracil and cisplatin (2 or 3 preoperative cycles and 3 or 4 postoperative cycles) significantly increased the curative resection rate, DFS, and OS in patients with resectable cancer. Phase II/III AIO-FLOT4 trial, Al-Batran et al compared perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) to the standard ECF regimen with a primary endpoint of pCR of the primary tumor. FLOT was associated with significantly higher proportions of patients achieving pCR than was ECF (16%; 95% CI, 10-23 vs. 6%; 95% CI, 3-11; P = 0.02). Additionally, FLOT was associated with a reduction in the percentage of patients experiencing at least one grade 3-4 adverse event. Although the NCCN guidelines recommend that patients with T2 stage or higher gastric cancer should prioritize perioperative chemotherapy + surgery, a treatment model of surgery + postoperative adjuvant therapy is more common in China. Therefore, the preoperative MDT discussion and a strengthened collaboration among the Departments of Surgery, Oncology, and Imaging are helpful and most important in optimizing patients' treatment plans. The recommendations of the NCCN guidelines for preoperative radiochemotherapy for gastric cancer are primarily based on the results of the CROSS study, which mainly enrolled patients with esophageal carcinoma and adenocarcinoma of the esophagogastric junction. Therefore, the recommendation level for preoperative radiochemotherapy in gastric cancer is not as high as that for perioperative chemotherapy, and more advanced evidence should be expected. In addition, special attention should be paid to the prevention and treatment of adverse reactions of the three-drug combination scheme. Even in the western population, the tolerability of the preoperative ECF/DCF/FLOT regimen remains worrisome; thus, optimization of the regimen and identification of appropriate candidates among the population should be implemented in the future.This edition of the guidelines adds a reasonable assessment on the efficacy of preoperative radiochemotherapy and emphasizes that patients who cannot achieve R0 resection after preoperative radiochemotherapy or who have undergone metastases during preoperative radiochemotherapy should be subjected to palliative supportive care.
We believe that failure of radiochemotherapy in these patients may indicate that the disease itself is highly invasive and has a poor prognosis. To some extent, if the metastases occur during preoperative radiochemotherapy, these patients may also suffer from tumor recurrence and metastasis long before they are directly treated with surgeries without neoadjuvant therapy. Therefore, preoperative radiochemotherapy can prevent unnecessary surgeries in this group of patients. However, this point of view remains an idea because designing a controlled clinical study to confirm it is currently impractical, and patients with limited-stage gastric cancer who would present metastases immediately after the surgery cannot be identified beforehand. However, we know that, as a whole, preoperative radiochemotherapy does increase the overall survival in patients with T2 stage or higher gastric cancer. Several questions, such as the optimization of preoperative radiochemotherapy regimens, value of immunotherapy in neoadjuvant therapy, and more accurate screening methods in identifying patients who can benefit from preoperative radiochemotherapy, are still worth studying.
MSI (dMMR) and PD-L1, following HER2, have become the recommended detection markers for advanced gastric cancer and are used to guide the application of anti-PD-1/PD-L1 immune checkpoint inhibitors. Currently, the primary existing problem is that the testing standards for MSI and PD-L1 have not been established, followed by the lack of qualification standards for the testing centers. Second, in addition to patients with advanced stage gastric cancer, the therapeutic value of the drug should be explored in the perioperative population.
The strict procedures for the comprehensive management of hereditary gastric cancer in our country are lacking, and preventive total gastrectomy has not been actively recommended and accepted. In this regard, patient and family education and collection of their pedigree data are necessary. Patients who have not undergone tumor resection should be strictly and regularly monitored.