In the discussion of the update to the 2009 edition of the NCCN clinical practice guidelines for gastric cancer, the panel continued to first point out that the treatment framework for gastric cancer is based on multidisciplinary collaboration and the correct assessment and staging of the disease. The initial diagnosis of gastric cancer is first based on evidence-based medicine, with a variety of tools such as imaging combined with endoscopy and systemic examination, followed by staging and diagnosis, and refinement of treatment decisions after overall planning.
Overview]
For early gastric cancer, the 2009 edition of the guidelines subdivides T1 staging into T1a and T1b. In situ (Tis) or T1a stage gastric cancer can be treated by endoscopic mucosal resection or can be treated by surgery only; locally progressive gastric cancer can be considered for more accurate staging by laparoscopic assessment of peritoneal dissemination status, and then appropriate treatment can be adopted.
For radical surgical treatment, Chinese experts still recommend D2 surgery (distal gastric cancer radical surgery) as the standard procedure for patients with locally progressive gastric cancer. The 2009 edition of the guidelines still emphasizes that the patient’s condition should be re-evaluated after surgical treatment, and treatment should be selected based on the patient’s stage, surgical modality, and postoperative recovery. Those with early gastric cancer combined with H. pylori (Hp) should undergo postoperative treatment to clear Hp infection (Figure 1 and 2).
[Neoadjuvant therapy].
For perioperative treatment, neoadjuvant therapy before resection of gastric cancer is still recommended in the 2009 edition of the guidelines, and the MAGIC study established the status of preoperative neoadjuvant chemotherapy as the standard treatment in the treatment of patients with resectable gastric cancer. As for the choice of chemotherapy regimen, other than ECF (epirubicin + cisplatin + 5-FU) regimen, other modified regimens such as ECX (epirubicin + cisplatin + capecitabine), EOF (epirubicin/oxaliplatin/5-FU), EOX (epirubicin + oxaliplatin + capecitabine) are also good choices as known from the results of the Real-2 study.
[Postoperative adjuvant therapy].
Post-operative adjuvant chemotherapy is recommended for stage II/III gastric cancer that has not received neoadjuvant chemotherapy
However, it has long been controversial whether patients who did not receive neoadjuvant chemotherapy with ECF regimen or other modified regimens before surgery should receive adjuvant chemotherapy after surgery. In the Japanese JCOG study, S-1 monotherapy as an adjuvant chemotherapy regimen after unified D2 radical surgery for stage II-III gastric cancer increased the 3-year survival rate of patients treated with postoperative adjuvant chemotherapy by 10% compared with the surgery-only group. However, there is no Western consensus on whether postoperative adjuvant chemotherapy alone can be beneficial. two meta-analyses were published in 2008, with 15, 3212 and 23, 4919 clinical randomized trials included and the number of cases, respectively. The results showed a trend toward improved 3-year survival, progression-free survival, and recurrence rates in patients who underwent adjuvant chemotherapy after surgery compared with surgery alone.
A recent meta-analysis of adjuvant chemotherapy in patients after radical surgery for gastric cancer above D1, which included 12 RCT studies, was published in 2009, and postoperative adjuvant chemotherapy reduced the risk of death by 22% compared with surgery alone. Only four of the meta-analyses were Japanese studies, while the remaining eight were European studies. The results were more credible and more instructive because of the strict inclusion criteria, which excluded studies containing only patients with stage T1 and studies with only D0 surgery, and were consistent with current clinical practice.
Therefore, for stage II/III patients who did not receive preoperative neoadjuvant chemotherapy with ECF regimen or other modified regimens, the Chinese expert group believed that they should still receive postoperative adjuvant chemotherapy, and this view was initially recognized by the US experts.
However, due to the complexity of adjuvant chemotherapy regimens included in various postoperative adjuvant chemotherapy meta-studies, the standard postoperative adjuvant chemotherapy regimen is not yet known. Safe and effective regimens in advanced gastric cancer can be selected with reference to the MAGIC study model, with fluorouracil-based drugs combined with platinum-based drugs, such as ECF regimen, modified ECF regimen, cisplatin or oxaliplatin combined with fluorouracil-based drugs, etc., while fluorouracil-based oral drugs can be used as single-drug adjuvant chemotherapy for early-staged and elderly patients. At the same time, patients can be encouraged to participate in clinical studies to explore the best treatment regimen and modality, which can be validated by large-scale randomized controlled studies.
Adjuvant postoperative radiotherapy is recommended for patients with D0/D1 postoperative gastric cancer
The INT116 study in the United States established the role of postoperative adjuvant radiotherapy. However, more than 90% of the cases included in this trial underwent D0/D1 resection, and D2 radical surgery has a different pattern of recurrence and metastasis than post-D0/D1 surgery. In the United States, the postoperative recurrence rate of residual gastric and surgical field lymph node recurrence was reported to be as high as 72% with conventional radical D0/D1 gastric cancer; in the Netherlands, the morbidity and mortality rate due to local recurrence in the surgical field was reported to be as high as 36% after D1 radical surgery, while it was reduced to 27% with D2 radical surgery; in clinical follow-up data from Japan, Korea and China, the recurrence of residual gastric or regional lymph nodes after D2 radical surgery was only about 25%, with peritoneal dissemination and lymph node metastasis were the most important prognostic influencing factors.
The results of these clinical observations suggest that local recurrence after radical D2 surgery is not the main long-term survival influencing factor, and whether postoperative radiotherapy will improve the long-term survival of patients after radical D2 surgery remains to be explored. In contrast, Korean scholars reported the results of a randomized controlled clinical study of patients with gastric cancer after D2-style surgery at the 2009 American Society of Clinical Oncology (ASCO) Gastrointestinal Oncology Symposium. In this study, one group was treated with XP regimen (capecitabine + cisplatin) combined with radiotherapy, and one group was treated with adjuvant chemotherapy with XP regimen alone. The safety comparison between the two treatment groups was initially reported at the meeting, but continued follow-up is needed for the differences in survival, and it is believed that the results will be made public in the next two to three years.
At present, for patients with gastric cancer after D0/D1 surgery (which is still mostly treated in China), postoperative radiotherapy can be used, otherwise postoperative adjuvant chemotherapy is used
Palliative chemotherapy for advanced gastric cancer]
FP regimen is recommended for category 2B as a three-drug combination with high toxicity
The FP (5-fluorouracil intravenous + cisplatin) regimen can bring an objective remission rate (RR) of 20%-30% and an overall survival (OS) of 8-9 months in patients with recurrent or metastatic advanced gastric cancer with a Karnofsky (KPS) score ≥ 60 or an ECOG systemic status score ≤ 2. Based on the limitations of basic medical insurance in China, this regimen is still recommended as a Class 2B regimen. This regimen remains as one of the recommended regimens in category 2B based on the limitations of basic health insurance in China. Adding epirubicin (ECF regimen) or docetaxel (DCF regimen) to this regimen can increase RR by about 10%-20% and OS by 1~2 months, but the incidence of adverse reactions is higher with the three-drug combination regimen for gastric cancer.
XP regimen becomes a class 2A recommendation
Cisplatin and 5-FU in the ECF regimen can be replaced by oxaliplatin and capecitabine, respectively. 2008 REAL-2 study published in the New England Journal of Medicine compared the efficacy of the ECF regimen and its three alternatives using a 2×2 analysis. The results showed that the EOX regimen had the longest OS (11.2 months) and was significantly better than the ECF regimen (9.9 months), and the ML17032 study again showed that the XP (capecitabine in combination with cisplatin) regimen may have an advantage in terms of RR, progression-free survival (PFS) and OS. The efficacy and safety of the XP regimen in Chinese gastric cancer patients was also confirmed by the results of a group of clinical trials in China, and therefore replacing 5-FU with cisplatin with capecitabine was recommended as a Class 2A regimen in the 2009 Chinese edition of the guidelines.
Multiple Treatment Options Recommended as Category 2B
In a randomized controlled study, 5-FU in combination with oxaliplatin was shown to be equivalent to cisplatin, but with a better safety profile. DCF improved RR and OS compared with CF, but had significantly increased toxicity, while paclitaxel had similar efficacy to docetaxel and lower myelotoxicity, so paclitaxel-based combination regimens are also an option for chemotherapy in advanced gastric cancer. Other options include irinotecan, which have yet to be expanded for clinical validation and are currently only recommended as Class 2B.
S-1 is not recommended for advanced gastric cancer
The oral fluorouracil formulation S-1, with tegafur, a precursor drug to 5-FU, as the active ingredient, was studied in a randomized controlled study conducted in the U.S. Although the results failed to show a better efficacy and survival advantage of S-1 in combination with cisplatin over 5-FU in combination with cisplatin, the safety profile was better, and its optimal dose and clinical efficacy need to be further explored. Pre-marketing clinical studies of S-1 in China also initially showed that S-1 in combination with cisplatin was superior to the FP regimen, similar to the results of clinical studies in Japan. However, since S-1 is not yet available in China, more clinical application experience and more clinical studies are needed to verify its efficacy, so domestic experts do not recommend its use in advanced gastric cancer patients in this edition of the guidelines.
Throughout the current multiple chemotherapy regimens, the efficiency of recurrent metastatic gastric cancer is maintained at 35%~45%, PFS is about 4~6 months, OS is 9~11 months, and no breakthrough has been achieved. Therefore, it is still recommended and encouraged for gastric cancer patients to participate in clinical research, especially in targeted drugs, new optimized protocols and individualized treatment in the future.
Prospect】：Targeted drugs and individualized treatment
The combination of different targeted drugs may change the existing treatment standard
The oncology community has started to experiment with multiple targeted therapeutic regimens for gastric cancer. Some classes of targeted drugs, such as epidermal growth factor small molecule tyrosine kinase inhibitors (EGFR-TKI), are currently seen to be ineffective in gastric cancer. Recent studies of bevacizumab in combination with a modified DCF regimen (FOLFOX regimen in combination with low-dose docetaxel) for advanced gastric cancer have shown impressive RR, PFS and OS of 64%, 12 months and 16 months, respectively.
About 50% of gastric cancers are known to express human epidermal growth factor receptor 2 (HER2), and studies of trastuzumab in combination with chemotherapy targeting this receptor have recently yielded results. Several domestic studies are also exploring the efficacy of XP regimens in combination with different targeted agents (including cetuximab and bevacizumab). We believe that these studies may yield new breakthroughs in the near future that will change the current standard of care for gastric cancer.
Optimal selection of new regimens and tumor markers become hot spots for research
The optimal selection of new regimens, such as two-drug combinations based on violet shirts and weekly or biweekly dosing, has also become one of the hot spots for research on the treatment of advanced gastric cancer. Most importantly, some studies have started to try to treat gastric cancer with individualized treatment mode, such as molecular markers like nucleotide excision repair cross-complementary gene 1 (ERCC-1) and microtubulin to guide chemotherapy with platinum and paclitaxel drugs, expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) in gastric cancer tissues to guide the fluorouracil-based drug application, etc., as well as tumor markers with clinical guidance that have not yet been agreed upon, but are believed to be generated in the future, thus truly achieving the goal of individualized treatment.