Gastrointestinal stromal tumor (GIST) is a disease that has become a classic model of molecularly targeted therapy for solid tumors in just over a decade since it first came into the limelight. During these ten years, thanks to the milestone success of the molecularly targeted drug Imatinib Mesylate in GIST, the diagnosis of GIST has been standardized, its pathogenesis has been studied in depth, and a large number of multicenter clinical studies have been completed or are underway at home and abroad. As of July 2010, a search of Pubmed for “Gastrointestinal stromal tumor” yielded more than 4,500 articles, thus GIST has undoubtedly become one of the hottest research topics in the field of GI tract tumors and solid tumors in recent years. With the advancement of molecular mechanism research, the treatment of GIST has evolved from simple surgical resection to comprehensive and individualized treatment including molecular target screening and treatment, surgical resection by multiple modalities, adjuvant therapy and neoadjuvant therapy. This article introduces the current consensus and new advances in the field of standardized treatment of GIST. 1.Application of multidisciplinary cooperation model in the treatment of GIST With the continuous subdivision of clinical specialties and the formation of subspecialties, the boundaries between various disciplines become more and more blurred, so the communication and collaboration between various disciplines become more and more important. The multi-disciplinary team (MDT) model of diagnosis and treatment has emerged. The MDT model has been widely applied and successful in diseases including breast cancer, colorectal cancer and gastric cancer. Therefore, MDT has become an important part of the clinical consultation process in various clinical practice guidelines. In the NCCN 2011 edition of GIST guidelines, it is clearly stated that all GIST patients need to be evaluated by an MDT team specializing in the relevant treatment before receiving treatment. Based on the characteristics of the GIST treatment strategy, the multidisciplinary team for GIST usually includes: gastrointestinal surgeons, gastrointestinal endoscopists, pathologists, diagnostic radiologists, basic oncology researchers, general internists, nurses, and social workers. The most important form of the MDT model is the regular, scheduled MDT meeting, which is a routine, periodic multidisciplinary consultation where the following basic tasks should be accomplished: clarifying the diagnosis, establishing the treatment process, establishing clinical decisions, and evaluating the results of the decisions for feedback. Since surgical treatment remains by far the most important part of GIST treatment, the multidisciplinary team should generally be led by a surgical specialist. The application of MDT in GIST treatment can be broadly divided into two parts: preoperative MDT and postoperative MDT. The role of preoperative MDT is: (1) to obtain a relatively clear preoperative diagnosis; (2) to exclude some cases without surgical indications; (3) to assess the resectability of surgery and develop surgical plans; (4) to assess comorbidities and surgical risks; and (5) to assess the indications for neoadjuvant therapy in some progressive cases. The role of the postoperative MDT is to The role of postoperative MDT is to (1) assess the risk of GIST after surgery; (2) grasp the appropriate adjuvant treatment indications; and (3) conduct standardized postoperative treatment and follow-up assessment. The author’s experience is that the MDT model is fundamental to ensure the best treatment for GIST patients. Since the establishment of the MDT team for GIST diagnosis and treatment in 2009, our unit has greatly improved the preoperative diagnosis of GIST, standardized surgical procedures, and established a reliable and clinically convenient postoperative follow-up treatment system, which has achieved the optimal individualized treatment as much as possible and attracted more and more GIST patients are increasingly being seen. It is recommended that all medical centers with conditions should establish and improve MDT model, follow the consensus clinical practice guidelines in clinical diagnosis and treatment, and determine the treatment and follow-up plan through the joint discussion of multidisciplinary experts, so that patients can receive the best treatment suitable for their conditions to prolong survival and improve the quality of life. 2. The significance of genotyping in GIST treatment In 1998, Hirota discovered the prevalence of functionally acquired mutations in the C-kit gene in GIST, which is an important milestone discovery in GIST research. Subsequently, a great deal of research has been conducted on the relationship between GIST and the C-kit gene and its later discovery, the PDGFRα gene. The common mutation loci known for GIST include exons 9, 11, 13, and 17 of the C-kit gene and exons 12, 14, and 18 of the PDGFRα gene. The significance of GIST genotype determination is mainly: (1) to help diagnose difficult cases (e.g., morphological observation of highly suspicious GIST but negative immunohistochemistry for CD117 and DOG-1); and (2) to predict the efficacy of targeted drug therapy. Mutations in exon 11 of the C-kit gene are the most sensitive to imatinib, followed by exon 9, while the sensitivity of exons 13 and 17 to imatinib treatment is not well defined. There are few data on the relationship between PDGFRα mutations and imatinib efficacy, but in vitro studies have shown that mutations in exons 12 and 14 are sensitive to imatinib, while mutations in exon 18, especially the D842V form, are resistant to imatinib. For example, the author once admitted a case of gastric giant GIST, the postoperative genotype was determined as PDGFRA D842V, which showed primary resistance to imatinib, so no adjuvant therapy was performed after surgery, and no recurrence has been seen since the long-term follow-up, avoiding the waste of resources and the economic burden and quality of life impact on patients brought about by inappropriate treatment; (3) may be able to predict the biological behavior of GIST. Whether mutations at different loci are related to the biological behavior of GIST is still controversial, and it is currently believed that the prognosis is influenced by the site of the primary tumor rather than the mutation site (e.g., C-kit exon 9 mutation has a poor prognosis because it occurs mostly in small intestine GIST, while PDGFRα mutation has a relatively good prognosis because it is commonly found in gastric GIST). However, a recent study has demonstrated that the prognosis of gastric GISTs with insertion/deletion mutations in exon 11 of the C-kit gene is poor. For these reasons, the NCCN guidelines affirm the role of genotype determination in predicting the efficacy of targeted therapy, and the Chinese consensus on the diagnosis and treatment of GIST also points out that genetic testing should be performed by a qualified laboratory for diagnosing difficult cases and cases to be treated with targeted drugs. 3.Surgical treatment of primary resectable GIST 3.1 Indications for surgery For limited gastric GIST less than 50px in diameter, the decision of follow-up or surgical resection should be based on the endoscopic ultrasound performance, with irregular margins, cystic changes, ulcers, strong echogenicity and heterogeneity suggesting high risk and requiring consideration of surgical resection, while asymptomatic gastric GIST without the above-mentioned manifestations can be followed up, but The advantages and disadvantages need to be fully explained to the patient to gain understanding. For the rest of GIST, regardless of the size, if the safety of surgical resection is guaranteed, surgery should be preferred in principle. In particular, rectal GIST, as the tumor increases in size, it will be more difficult to perform anus-preserving surgery, so it should be actively treated surgically. For GIST with limited but high risk of surgical resection, which may have obvious organ function or resectability in critical state, imatinib treatment should be performed first after biopsy to obtain pathological evidence, and then surgical treatment should be performed after the tumor reaches maximum response. 3.2 Surgical principles The goal of GIST surgery is to obtain R0 resection. It should be emphasized that every possible effort should be made to avoid tumor rupture during surgery, as it is very likely to lead to intra-abdominal dissemination and postoperative recurrence. For GIST with adhesions to adjacent organs, a combined organ resection with whole block resection is required. The extent of surgical resection for GIST needs to be decided according to the specific site of the tumor, with emphasis on ensuring negative margins, so gastric GIST is often performed by local or wedge resection of the stomach, and small bowel GIST is often performed by resection of the intestinal segment. However, GIST near the cardia or pylorus often requires a hemi-gastrectomy to ensure a patent digestive tract. Duodenal and rectal GISTs have certain specificities and should be considered on a case-by-case basis, such as local resection + intestinal wall repair, duodenal resection, major gastrectomy, pancreaticoduodenectomy, etc., and rectal GISTs can be resected via anus, transabdominal anterior resection or combined abdominal perineal resection. However, pancreaticoduodenectomy and combined abdominal-perineal surgery should be avoided as much as possible to improve patients’ quality of life, which may be achieved by preoperative application of imatinib to shrink the tumor. 3.3 Regarding laparoscopic and endoscopic surgery, the use of laparoscopic surgery in the treatment of GIST has always been controversial, and the focus of the controversy is mainly on the tumor-free operation and safety of the surgery. Since GIST tumors are brittle and have no envelope, they are prone to rupture during surgery, so laparoscopic surgery is not recommended in previous guidelines. However, with the maturation of laparoscopic surgery and the success of laparoscopic treatment for GIST, tumor size is no longer an absolute contraindication to laparoscopic surgery. The latest NCCN guidelines state that for GIST in some appropriate sites (e.g., antrum or greater curvature of the stomach, jejunum), surgery can be performed by physicians with extensive experience in laparoscopic surgery. The author, combined with the experience of his unit, believes that laparoscopic surgery is safe and feasible for GISTs less than 125 px in diameter at the above sites, and that surgical options for GISTs larger than 125 px in diameter should be carefully considered and can be included in prospective clinical studies and accomplished with the assistance of a hand-assisted laparoscope. Endoscopic surgery for gastric GIST is still in the exploratory stage. Since GIST mostly originates from the intrinsic muscular layer of the stomach, endoscopic treatment is likely to result in inadequate resection and affect the radicality, and often requires endoscopic full-thickness resection (EFR) of the gastric wall, with metal clamps to close the incised gastric wall from the gastric cavity after resection. The incidence of post-operative gastric leak is certain. Recently, laparoscopic and laparoscopic cooperative surgery (LECS) has been applied in the treatment of GIST, which not only allows accurate localization and timely management of perforation, but also allows observation of the complete resection of the tumor, whether there is intracavitary bleeding after resection, and whether the closure is tight. LECS not only can accurately localize the perforation, but also can observe whether the tumor is completely resected, whether there is internal bleeding after resection, whether the closure is tight and whether the gastric lumen is narrowed after closure, thus avoiding the occurrence of related complications and increasing the safety and effectiveness of the surgery. 4. Treatment of recurrent metastatic GIST For the majority of recurrent metastatic GIST, targeted drug therapy is the preferred treatment modality. The first-line drug is imatinib and the second-line drug is sunitinib. It is inconclusive whether surgery can improve the prognosis of patients with relapsed or metastatic GIST in targeted therapy, pending prospective controlled clinical studies. For recurrent or metastatic GIST, surgical resection followed by targeted drug therapy is feasible if it is clear from MDT discussions that complete resection of all lesions is possible without significant surgical risk. For the rest of recurrent or metastatic GIST, in principle, imatinib is preferred. If the disease is in remission during the treatment process, surgical resection can be considered for those with resectability; local progressive lesions that appear during the overall remission of the disease can also be surgically resected, which can achieve the effect of reducing tumor load and improving life treatment. 5.Neoadjuvant therapy for GIST The concept of neoadjuvant therapy was first proposed by Frei in 1982, initially focusing on solid tumors such as head and neck cancer and breast cancer, updating the previous tradition of chemotherapy timing. Since then, neoadjuvant therapy has been increasingly used in other tumors such as progressive gastric cancer. Due to the miraculous efficacy of imatinib in the treatment of metastatic recurrent and unresectable GISTs, preoperative neoadjuvant treatment with imatinib for GISTs whose tumors cannot be completely resected or are at great risk of resection has now become a new hot spot for research. Similar to neoadjuvant therapy for other solid tumors, the objectives of neoadjuvant therapy for GIST are: to reduce the clinical stage and grade of the tumor; to reduce the risk of surgery and to maximize the preservation of vital organ function; to increase the chance of surgical or radical resection; to kill subclinical metastases outside the surgical area; to prevent medical tumor dissemination; to spare unnecessary surgery for those with rapidly progressing tumors or those who are insensitive to drugs; and to prevent tumor response to drugs. It is important to obtain in vivo drug sensitivity information to provide a basis for postoperative drug selection. The current NCCN guidelines recommend neoadjuvant therapy with imatinib (the latest version is called preoperative therapy) for GISTs that are locally progressive or potentially resectable, GISTs that are critically resectable, or GISTs with a high potential for surgical complications; the ESMO guidelines recommend neoadjuvant therapy for GISTs that cannot be resected with R0, GISTs with a high potential for surgical damage to adjacent organs, and GISTs that, in the judgment of the operator, can be treated with neoadjuvant therapy. The ESMO guidelines recommend neoadjuvant therapy for GISTs that cannot be resected with R0, GISTs with a high likelihood of surgical damage to adjacent organs, and GISTs for which neoadjuvant therapy, in the judgment of the surgeon, can increase the safety margin of surgery. The duration of neoadjuvant therapy is determined by the response to treatment, and it is generally accepted that it should be chosen when the maximum response to treatment has been achieved and the tumor has not progressed. The duration of neoadjuvant therapy is recommended by NCCN for 3-6 months and by ESMO for 6-12 months, and by domestic expert consensus for primary resectable GIST, the duration of neoadjuvant therapy should not exceed 6 months. 6. Adjuvant therapy for GIST The great success achieved by imatinib in the treatment of progressive gastrointestinal mesenchymal tumors has greatly encouraged the confidence of investigators in the further role of the drug. Determining the status of imatinib in adjuvant therapy was the famous Z9001 trial, which found that the postoperative application of imatinib 400mg/d in patients with >75px non-metastatic GIST significantly improved the 1-year survival rate compared to the placebo group (98% vs 83%), suggesting that this group of patients benefited from adjuvant therapy. The US FDA has approved imatinib in 2008 for postoperative adjuvant therapy in GIST patients with high risk of recurrence. The current NCCN guidelines recommend postoperative adjuvant treatment with imatinib for at least 1 year in patients with high-risk GIST, noting that discontinuation of the drug will increase the risk of disease recurrence and that the optimal duration of adjuvant therapy has not yet been reached. Domestic expert consensus suggests that imatinib should be applied adjuvantly for 1 year after surgery for intermediate-risk GIST patients and at least 2 years for high-risk patients. Recently, data from a European open phase III clinical study, SSGXVIII/AIO, have been published, which enrolled 400 high-risk GIST patients and randomized them 1:1 into 2 groups, with one group receiving 400 mg/d imatinib for 1 year and the other group receiving the same treatment for 3 years, comparing the relapse-free survival (PFS) and overall survival ( OS). Analysis of follow-up data through the end of 2010 showed a significant increase in PFS (65.5% vs. 47.9%) and OS (92% vs. 81.7%) in the 3-year treatment group compared with the 1-year treatment group. The conclusion suggests that the 3-year regimen can be used as a postoperative treatment for high-risk patients. In conclusion, standardized and comprehensive treatment is in line with the latest concepts of surgical treatment, which is the way to improve the outcome of the disease. As the research on GIST continues to deepen and the treatment experience continues to accumulate, the standard of care for GIST will be further improved.