Gastric cancer is an important disease that seriously threatens human health. China is a country with a high incidence of gastric cancer, accounting for about 47% of the global incidence, with 460,000 new cases and more than 350,000 deaths from gastric cancer each year [1]. Unfortunately, the internal medicine treatment of gastric cancer is still very tricky, and the current treatment options are far from satisfactory. Individualized medical treatment is an important way to improve the overall outcome of gastric cancer, and the authors only review the relevant progress in recent years. 1. High heterogeneity of gastric cancer determines the necessity of individualized treatment Gastric cancer is a group of highly heterogeneous diseases. Gastric cancers with different geographic distribution, pathological types, genetic factors and sites of occurrence differ greatly in terms of pathogenic factors, disease behaviors, clinical course and prognosis. In terms of geographical distribution, the overall incidence of gastric cancer in some western countries has been decreasing year by year since World War II, but the incidence of proximal gastric cancer, especially cancer of the gastroesophageal junction, has been gradually increasing and has surpassed that of distal gastric cancer. In countries with high incidence, such as Japan and China, although distal gastric cancer is still a common type, proximal gastric cancer also shows an obvious rising trend. In recent years, although the incidence ranking of gastric cancer among malignant tumors in China is decreasing, the absolute number of incidence is still rising, and with reference to the situation in some East Asian countries, it is estimated that there will be no significant decrease in the future. From the etiological point of view, H. pylori infection is an important causative factor of gastric cancer. It is estimated that 63.4% of gastric cancers worldwide are related to H. pylori infection, but studies have shown that H. pylori infection is the main risk factor for gastric cancer, especially distal gastric cancer, and has nothing to do with the development of gastroesophageal junction cancer, and some studies have even shown a negative correlation between the two; while obesity and gastroesophageal reflux disease are more closely related to gastroesophageal junction cancer. H. pylori not only affects the biological behavior and clinical course of gastric cancer, but also has a significant impact on the choice of treatment options. Some studies have shown that H. pylori eradication therapy after surgery for early gastric cancer significantly reduces the rate of disease recurrence. As early as 1965, Lauren classified gastric cancer into intestinal type and diffuse type according to the tumor growth pattern, which is another simple but important, widely recognized and long-standing pathological classification standard for gastric cancer in addition to WHO pathological staging. Intestinal type gastric cancer has glandular-like structure and expansive growth in the gastric wall, which is the main pathological type of distal gastric cancer, mostly occurs in the gastric sinus and originates from multifocal atrophy and intestinalization caused by Helicobacter pylori. The diffuse type, on the other hand, shows a single loss of adherent cells and infiltrative growth, mostly originating from the gastric mucosa without atrophy and manifesting as superficial gastritis due to H. pylori. The intestinal type of gastric cancer is more common in men and older patients and has a slightly better prognosis. Diffuse gastric cancer, on the other hand, is more common in women and younger patients less than 50 years old, and has a poor prognosis. In high-incidence countries (including China), intestinal gastric cancer is still the main pathological type; the continuous decline in the incidence of gastric cancer in some western countries is mainly manifested by the decline of intestinal gastric cancer, making diffuse gastric cancer a more common pathological type. There is no doubt that the marked differences in the geographical distribution, causative factors and pathological types of gastric cancer can have an important impact on the choice of treatment options and the assessment of patients’ prognosis. Unfortunately, our knowledge of these characteristics is not sufficient, and we lack our own experience, learn more from them than innovate them, emphasize normative “guidelines”, and intentionally or unintentionally ignore individualized practice. 2. There are many studies on gastric cancer chemotherapy, but there is no breakthrough. The 5-year survival rate of gastric cancer in China is less than 20%. At present, the commonly used combination chemotherapy regimen can only improve the median survival time of advanced gastric cancer to about 10 months [8]. Clinical studies have found that there are several chemotherapeutic drugs with anticancer activity against gastric cancer, and in addition to the classical cisplatin and fluorouracil, doxorubicin, epothilone, oxaliplatin, and irinotecan also have better efficacy against gastric cancer; the application of new generation fluorouracil drugs, capecitabine and S-1, has further improved the effectiveness and safety of these drugs. However, even so, the survival time of advanced gastric cancer is hardly to exceed 12 months. The choice of chemotherapeutic drugs for gastric cancer around the world, like most solid tumors, is mostly based on the results of respective clinical studies. In terms of adjuvant chemotherapy, the United States has determined that patients with D0 and D1 resection can benefit from postoperative fluorouracil combined with radiotherapy based on the results of the early INT 0116 study, although controversial; in Europe, especially in the United Kingdom, perioperative chemotherapy with ECF regimen is recommended based on the results of the MAGIC study; and in Japan, adjuvant chemotherapy with S-1 monotherapy is recommended based on the results of the ACTS-GC study. The CLASSIC study reported by Korean scholars in 2011 showed that the XELOX regimen significantly reduced the risk of recurrence in stage II to stage IIIB D2 resected gastric cancer, and patients with late surgical stage had more benefit [12]. An analysis of these two studies from East Asia suggested that single-agent S1 has mild adverse effects and is well tolerated and may be more suitable for patients with relatively early surgical staging, while the combination regimen is more intense, has more adverse effects, and is a better choice for patients with late surgical staging. All of these findings from different countries currently lack high-level evidence-based medicine from large multicenter groups conducting direct controlled studies. The situation is even more complicated in the case of palliative chemotherapy for advanced gastric cancer. The European REAL-1 and REAL-2 studies mostly used ECF or its derivative EOX regimens[; the United States, based on the results of the V325 study, preferred to apply the DCF regimen, and later, due to too many toxic side effects, some used the mDCF regimen; Japan recommended the application of the CS regimen (S-1 combined with cisplatin) based on the results of SPIRITS. In addition, palliative chemotherapy regimens containing capecitabine and oxaliplatin have been studied in Korea. It should be noted that there are few direct controlled studies on these regimens, and the advantages and disadvantages of these regimens have yet to be tested, and there is no unified understanding of them, so there is no standard first-line regimen for gastric cancer worldwide. The underlying reason is the complexity of treatment due to the heterogeneity of gastric cancer. In addition, for reasons that are not yet known, the efficacy of different regimens for gastric cancer in different regions and ethnicities may indeed differ geographically and even racially. The involvement of commercial factors is not even excluded. In 2006, the Japanese SPIRITS study showed “encouraging” results: the CS regimen was 54% effective, with an overall survival time of 13 months[; however, the FLAGS study, which used a similar regimen in a Western population with advanced gastric cancer, was disappointing, showing that the median survival time in the S-1 combined with cisplatin group was the same as that in the fluorouracil combined group. Survival time was not significantly different from that of the fluorouracil combined with cisplatin group (8, 6 months vs. 7, 9 months, P=0, 1983), and progression-free survival was similar (4, 8 months vs. 5, 5 months, P=0, 9158). The investigators explained this difference by the higher CYP2A6 enzyme activity and larger body surface area in the Western population compared to the Japanese and the low dose of S-1 administration . However, this may be only part of the reason, and other explanations should include that the disease characteristics of Western and Japanese gastric cancer are inherently very different. In fact, many reports in the literature also confirm that the type of pathology is an important factor in the superior prognosis of gastric cancer in eastern high-incidence countries compared to western countries. This is because, studies have shown that the median survival time for intestinal type gastric cancer, which is predominant in Eastern high-incidence countries, is about 10 months, while diffuse type gastric cancer, which is prevalent in Western countries, is only 6-8 months. The dilemma we face in gastric cancer chemotherapy is mainly due to the lack of understanding of the biological characteristics of gastric cancer, the lack of effective biological difference analysis of patients, and the lack of biomarkers related to the efficacy to guide the clinical use of drugs, and the inability to implement individualized medical treatment for patients. With the advent of targeted therapy, the individualized medical treatment that people have been pursuing has gradually become a reality. It has been found that KRAS gene mutation is associated with EGFR monoclonal resistance, thus saving 30-50% of advanced colorectal cancer patients from the ineffective treatment of EGFR monoclonal resistance. First-line treatment with EGFR-TKIs in patients with EGFR mutations has also been found to be more than 70% effective in advanced non-small cell lung cancer studies. Research on targeted therapies for gastric cancer began relatively late, but several studies have explored molecularly targeted agents in combination with chemotherapy for advanced gastric cancer. Among these, the ToGA study is the most impressive. In the study, the addition of trastuzumab could extend the median survival time of patients with advanced gastric cancer by nearly 3 months compared to chemotherapy alone, reaching 13, 8 months, which set the best-ever survival score for advanced gastric cancer. And subgroup analysis showed that patients with high HER2 expression (IHC2+/FISH+ or IHC3+) could achieve an amazing overall survival time of 16, 0 months with trastuzumab. It was also found that the rate of HER2 positivity was influenced by various factors such as tumor site and pathological type. Gastroesophageal junction cancer had a higher HER2 positivity rate than gastric cancer, 33, 2% and 20, 9%, respectively (P<0, 001< span="">). There was also a significant difference in HER2-positive rates between intestinal and diffuse/mixed gastric cancers, with 32, 2% for intestinal and 6, 1/20, 4% for diffuse/mixed (P<0, 001< span="">), respectively. The ToGA study was successful by screening 3807 patients, with only 594 HER2-positive patients eventually entering the clinical study. This study also ushered in a new era of individualized medicine for gastric cancer. The AVAGAST study is an international multicenter phase III clinical study of bevacizumab in combination with chemotherapy for the treatment of advanced gastric cancer. The study did not find an overall survival benefit from the addition of bevacizumab for advanced gastric cancer, but showed significant regional differences. The greatest survival benefit from bevacizumab was seen in the US enrollment (6, 8 months vs. 11, 5 months), followed by the European enrollment (8, 6 months vs. 11, 1 month), with little such benefit observed in the Asian enrollment (12, 1 month vs. 13, 9 months). A meta-analysis published by ASCO in 2011 further suggested that the survival benefit of bevacizumab in combination with chemotherapy for advanced gastric cancer is influenced by the site of primary focus and pathological staging, with a greater survival benefit for gastroesophageal junction cancer and a poorer outcome for diffuse gastric cancer, with median survival times of 20 and 12 months, respectively. The median survival time was 20 and 12 months, respectively (P=0,02). Another EXTRA study completed in China showed that the first-line treatment of advanced gastric cancer with cetuximab combined with capecitabine + cisplatin had an efficiency of 53.2% and a median survival time of 11.5 months. Although there was also good efficacy, the lack of a validated biomarker as a screening indicator for enrollment made this study much less clear in terms of clinical benefit than the ToGA study. Further analysis of the EXTRA study revealed that the severity of rash occurring in patients was strongly correlated with clinical outcomes, with patients with severe rash having an effective rate of 76.5%. EGFR expression was significantly correlated with rash, with the incidence and severity of rash increasing as EGFR expression increased. It indicates that there are indeed some patients who can benefit from EGFR-targeted therapy, and there is an urgent need for clinical screening of these patients based on certain biological markers before administering the therapy, and the ongoing phase III EXPAND study will continue to explore the effectiveness and relevant biomarkers of cetuximab for gastric cancer. In malignant cancer treatment, efficacy prediction has always been a difficult issue, and a large number of patients with ineffective treatment not only have to suffer from the adverse effects of antitumor therapy, but also have to bear a heavy financial burden. If specific markers can be used to accurately predict the efficacy of treatment, it is of great practical significance to improve the efficiency of treatment, reduce the economic and time wastage of patients, and avoid unnecessary toxic side effects. However, the individualized research of gastric cancer chemotherapy is still foggy and more breakthroughs are needed. By reviewing some important clinical studies on gastric cancer, it is easy to find that different countries and regions apply different treatment protocols according to their own habits for various reasons, and clinical studies on gastric cancer also revolve around their own protocols, which obviously increases the difficulty of obtaining reasonable evidence-based medical evidence. For example, Europe is accustomed to applying ECF regimen, so the famous MAGIC and REAL series of studies are centered on this regimen or its modification; the United States is accustomed to applying DCF regimen, and although the V325 study showed that this regimen has limited survival benefit and significant toxic side effects, the NCCN guidelines still recommend it as the first-line standard treatment regimen for advanced gastric cancer (Class I consensus); and Japan The S-1-containing regimen is highly recommended in the Japanese Gastric Cancer Management Statute. As the original Japanese drug, S-1 has become the core drug for gastric cancer in Japan, and various studies on gastric cancer have been conducted around S-1, which has now been promoted to the forefront of gastric cancer treatment – used in adjuvant therapy. Although, the biological behaviors of gastric cancer in China and Japan are similar in many aspects, and there are commonalities in treatment choices, more and better evidence is needed to support and validate the rational application of S-1 [. Based on the results of the REAL-2 study, it is reasonable to apply the EOX regimen instead of the ECF regimen in advanced gastric cancer. It is also due to this study that a number of studies have been or are being conducted to compare the safety and efficacy of oxaliplatin and cisplatin, as well as oral and intravenous fluorouracil analogues [27,28]. However, it should be noted that oxaliplatin and cisplatin are similar drugs, not the same drug, with differences in their antitumor spectrum, no cross-resistance, and no clinical applications that can be applied interchangeably at will [29]; similarly capecitabine and S-1 instead of 5-FU have to be implemented based on evidence-based medical evidence, otherwise it will significantly increase the economic burden of patients. As far as the available evidence is concerned, there are already some options in the individualization of targeted therapy for gastric cancer. For example, trastuzumab combined with chemotherapy is a good choice for HER2-positive gastric cancer, while bevacizumab is less effective for gastric cancer in Asians, and should be chosen for use with great caution until new evidence is available. However, there are not many high-level clinical studies that can reflect the characteristics of gastric cancer in China, which is far from meeting the needs of gastric cancer clinical practice. Most of the clinical studies in China refer to those in Europe, America and Japan to formulate and implement treatment plans. However, since gastric cancer is highly heterogeneous and the incidence, causative factors, disease characteristics and clinical efficacy of gastric cancer vary greatly from region to region, it is inappropriate to apply foreign clinical studies only to guide our own clinical practice. The Japanese “Statute for the Management of Gastric Cancer” clearly states that the management of gastric cancer in Japan should be implemented based on evidence from clinical studies in the country, which is worthy of our reference.