In recent years, the diagnosis, treatment and research of gastrointestinal stromal tumors (GIST) have progressed rapidly. In order to promote the standardized diagnosis and treatment of GIST and to establish a clinical multidisciplinary cooperation model including pathology, radiology, surgery and medical oncology, it is necessary to develop expert consensus or clinical practice guidelines as an important reference. In this regard, the previous Chinese GIST Diagnosis and Treatment Expert Consensus (2009 version) has played an active role, and during the CSCO Annual Meeting in September 2010, the GIST Expert Committee suggested to update this expert consensus (2009 version), which was then widely consulted, discussed and revised several times, and recently supplemented with the latest information in 2011. This paper is now published.
Part I. Principles of pathological diagnosis
1. Definition of GIST
GIST is the most common mesenchymal-derived tumor of the gastrointestinal tract, driven by mutated c-kit or platelet-derived growth factor receptor (PDGFRA) genes; histologically it is mostly composed of spindle cells, epithelioid cells, even or pleomorphic cells, arranged in bundles or diffuse images, and is usually positive for CD117 and/or DOG-1 expression by immunohistochemistry.
2. Requirements for specimens
Post-surgical specimens must be fixed promptly, and specimens should be sent to the pathology department within 30 minutes of dissection and fixed by complete immersion in sufficient neutral 10% formalin solution (at least 3 times the volume of the specimen) [1]. For tumor tissues ≥2 cm in length, they should be cut at 1 cm intervals to achieve full fixation. The fixation time should be 12~48h to ensure the feasibility and accuracy of subsequent immunohistochemistry and molecular biology detection. If possible, fresh tissues should be properly frozen for future molecular genetic study.
3.The pathological diagnosis of GIST based on
3.1 Basic diagnosis
Histologically, GIST can be divided into three major categories based on cell morphology: spindle cell type (70%), epithelioid cell type (20%) and mixed spindle cell/epithelioid cell type (10%). Immunohistochemical tests showed a CD117 positivity rate of approximately 95%, DOG-1 positivity rate of 98%, CD34 positivity rate of 70%, α-SMA positivity rate of 40%, S-100 protein positivity rate of 5% and Desmin positivity rate of 2% [2-4]. Diagnostic ideas and criteria.
(i) The diagnosis of GIST can be made for cases with histological patterns consistent with GIST and positive for CD117;
(ii) The diagnosis of GIST can be made for tumors with histological pattern consistent with GIST but CD117 negative and DOG-1 positive;
③Tumors with histologic pattern consistent with GIST but negative for both CD117 and DOG-1 should be referred to a specialized molecular biology laboratory to test for mutations in c-kit or PDGFRA genes to help clarify the diagnosis of GIST. If mutations in this gene are present, the diagnosis of GIST can be made;
④ In cases with a histologic pattern consistent with GIST but negative for both CD117 and DOG-1 and without mutations in the c-kit or PDGFRA genes, a possible diagnosis of GIST can be made if other tumors such as smooth muscle tumors and neurogenic tumors can be excluded. See Figure 91-1.
3.2 Genetic testing
Genetic testing should be performed in a qualified laboratory, and polymerase chain reaction (PCR) amplification-direct sequencing is recommended to ensure the accuracy and consistency of the test results.
Gene mutation testing is important to help diagnose difficult cases, predict the efficacy of molecularly targeted therapeutics, and guide clinical treatment. The expert committee recommends that genetic analysis should be performed when the following conditions exist.
(i) All initially diagnosed recurrent and metastatic GISTs that are proposed for molecular targeted therapy;
②After surgery for primary resectable GIST with moderate to high risk of recurrence, imatinib adjuvant therapy is indicated;
③In difficult cases, c-kit or PDGFRA mutation analysis should be performed to clarify the diagnosis of GIST;
④Differentiate between NF1 GIST, complete or incomplete Carney’s triad, familial GIST, and pediatric GIST.
GIST, complete or incomplete Carney’s triad, familial GIST, and pediatric GIST; ⑤ identify simultaneous and heterochronous multiple primary GIST [5]. The loci to be tested for mutations should include at least exons 11, 9, 13 and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene. Since the majority of GISTs (65%-85%) have mutations in exons 11 or 9 of the c-kit gene [6-8], for patients with limited affordability, these two exons can be prioritized for differential diagnosis; however, for patients with secondary drug resistance, additional testing of exons 13, 14, 17, and 18 of the c-kit gene is advisable.
3.3 Risk assessment for primary completely resected GIST
The risk assessment for limited GIST should include the site of the primary tumor, the size of the tumor, the nuclear split pattern, and whether rupture has occurred. The 2002 version of the National Institutes of Health (NIH) risk classification [9] has been used, including the size of the tumor and the number of nuclear divisions per 50 high-powered views (data in Table 1 are based on a 0.65 microscope lens; the 50 high-powered views where nuclear divisions are abundant must be counted). Several retrospective studies have confirmed that both of these indicators are associated with a poorer prognosis for GIST originating in the stomach than for GIST originating in the stomach) and tumor rupture as basic indicators of prognosis. See Table 91-1 for details.
Some experts believe that in clinical practice, relying on the above factors alone to assess GIST risk classification may still be inadequate, and that other tumor pathological features, such as significant tumor cell heterogeneity [11], depth of tumor invasion, degree of surrounding organ invasion (note: surrounding organ infiltration is not considered limited GIST, but progressive GIST), vascular and nerve infiltration [12, 13], and tumor thrombus formation, etc., are also important for the assessment, staging, and grading of the biological behavior of GIST [14, 15]. The complete resected limited GIST can be differentiated into benign, potentially malignant and malignant based on morphological features
benign, potentially malignant, and malignant. The minimum criteria for the diagnosis of malignant GIST are the presence of one of the following morphological features: significant heterogeneity of tumor cells, tumor necrosis, myxoid infiltration, ancient coin-like growth around blood vessels, nuclear schizophrenia ≥ 10/50 HPF; mucosal infiltration, nerve infiltration, fatty infiltration, vascular infiltration and lymph node metastasis; the more of the above indications, the higher the degree of malignancy. The relationship between this morphological pattern and biological behavior can be helpful in guiding adjuvant therapy and assessing prognosis, but further evidence-based evidence is needed. The relationship between this morphological pattern and biological behavior can help guide adjuvant therapy and assess prognosis, but further evidence-based medical evidence is needed to fully support and incorporate the clinical situation.
4. Standardization of GIST pathological diagnosis report
The pathology report should be standardized and meticulous, and must accurately describe the primary site, tumor size, nuclear schizophrenia and tumor rupture, and also record other indicators suggestive of malignancy, including important information such as margin condition, risk assessment, immunohistochemical testing and other pathological reference indicators related to prognosis (except for puncture specimens). Surgical surgeons should take care to describe and provide indicators that affect prognosis during surgery.
Part II Principles of Surgical Treatment
1. Principles of biopsy
It is estimated that surgery can be performed directly if complete resection is possible and the function of related organs is not seriously affected. Recent NCCN guidelines [16] have clarified that biopsy is required if neoadjuvant therapy is to be performed. It should be noted that inappropriate biopsy may cause tumor rupture, bleeding and increase the risk of tumor dissemination; especially for deeper sites, such as tumors located in the duodenum, biopsy should be performed with caution.
1.1 Pre-surgical biopsy
①For most GISTs that can be completely resected, routine biopsy or puncture before surgery is not recommended.
②For those who need combined multiple organ resection, or whose function may be affected by related organs after surgery, preoperative biopsy can be considered to clarify the pathological diagnosis and help decide whether to operate directly or to treat with preoperative medication first;
③ For lesions that cannot be resected or are estimated to be difficult to obtain R0 resection and are intended to be treated with preoperative medication, a biopsy should be performed first;
④Percutaneous puncture, for patients whose tumor has disseminated or recurred.
⑤ For patients with primary and suspected GIST, if the nature needs to be clarified preoperatively (e.g. exclude lymphoma), ultrasound endoscopy-guided aspiration biopsy is preferred; ultrasound endoscopy-guided aspiration biopsy has a low probability of causing intracavitary implantation;
(6) For rectal and pelvic masses, if preoperative biopsy is required, transrectal anterior wall aspiration biopsy is recommended; (7) biopsy, which should be performed by experienced surgeons.
1.2 Fine needle biopsy
With ultrasound-guided fine-needle aspiration (EUS-FNA), the concordance with the expression of immunohistochemical staining of surgical specimens can reach 91% and the diagnostic accuracy 91%. In patients with high-risk EUS features, puncture biopsy is not performed and the lesion is directly surgically excised.
1.3 Endoscopic biopsy
It is often difficult to make a definite pathological diagnosis by relying on endoscopic guided biopsy, because tumor tissue can only be obtained when GIST involves the mucosa; and it may occasionally lead to severe bleeding of the tumor, which needs to be performed with caution.
1.4 Intraoperative frozen biopsy
Intraoperative freeze biopsy is not routinely recommended. Unless there is a suspicion of peripheral lymph node metastasis or other malignant tumors cannot be excluded during surgery.
2. Indications for GIST surgery
① For limited GIST with maximum tumor diameter >2cm, surgical resection is in principle feasible; for unresectable limited GIST, or those who can be resected at the borderline, but the risk of resection is high or the function of organs is seriously affected, preoperative drug therapy is recommended first, and surgery will be performed after the tumor shrinks.
② For suspected limited GIST with maximum tumor diameter ≤ 2 cm, symptomatic patients should undergo surgery. Asymptomatic GIST located in the stomach, once diagnosed, ultrasound endoscopic risk grading should be determined based on its presentation (adverse factors are irregular border, ulceration, strong echogenicity and heterogeneity). If combined with adverse factors, resection should be considered; if no adverse factors are present, ultrasound endoscopy can be reviewed periodically. For GIST located in the rectum, early surgical resection is preferred because of the higher malignancy and the corresponding increase in surgical difficulty in preserving anal function once the tumor increases in size.
(③) Recurrent or metastatic GIST is treated differently in the following cases: without molecular targeted drug therapy, but it is estimated that complete resection can be achieved and the risk of surgery is not significant, drug therapy can be recommended or surgical resection of the entire lesion can be considered. For recurrent or metastatic GIST with effective molecular targeted drug therapy and stable tumor maintenance, if all recurrent metastatic lesions are estimated to be resectable, surgical resection of all lesions is recommended. For relapsed metastatic GIST with limited progression, given that the overall control is more satisfactory after molecular targeted drug therapy and often only a single or a few lesions progress, surgical resection can be considered carefully for patients in good systemic condition. Intraoperatively, progressive lesions are removed and as many metastases as possible are removed to complete a more satisfactory tumor reduction surgery. Recurrent metastatic GIST with extensive progression under molecular targeted drug therapy is in principle not considered for surgical treatment. Palliative tumor reduction surgery is limited to cases where the patient can tolerate the surgery and where the surgery is expected to improve the patient’s quality of life.
④ Indications for emergency surgery: Emergency surgery is required when GIST causes complete intestinal obstruction, gastrointestinal perforation, gastrointestinal hemorrhage where conservative treatment is ineffective, and abdominal hemorrhage caused by spontaneous rupture of the tumor.
3.Surgical principles of GIST
3.1 Surgical principles
① The goal of surgery is to achieve R0 resection as much as possible. If the initial surgery is only for R1 resection, a second surgery can be considered if the difficulty of re-operation is expected to be low and the risk can be controlled without causing damage to the major functional organs. Lymph node metastasis is rare in GIST, and routine debulking is usually not necessary unless there are clear signs of lymph node metastasis.
② Tumor rupture and bleeding: one of the reasons is spontaneous bleeding which occurs less frequently, and the other reason is improper touching of tumor during surgery which causes rupture and bleeding; therefore, intraoperative probing should be careful and gentle.
③ Positive postoperative incision margin: At present, domestic and foreign scholars tend to adopt molecular targeting drug treatment.
3.2 Laparoscopic surgery
Laparoscopic surgery is easy to cause tumor rupture and lead to abdominal implantation, so it is not recommended for routine application. If the tumor diameter is ≤5 cm, laparoscopic resection can be considered in an experienced center [17]. Intraoperative use of a “retrieval bag” is recommended, with special attention to avoid tumor rupture and dissemination. For tumors >5 cm, laparoscopic surgery is not recommended in principle, except for clinical studies [18].
3.3 Gastric GIST surgery
Local resection, wedge resection, subtotal gastrectomy or total gastrectomy with a 1-2 cm margin and meeting the R0 resection requirement is generally adopted. Proximal gastrectomy is indicated for GISTs that may cause cardia stenosis after resection and suturing. Total gastrectomy can be performed for multifocal, large GIST or concomitant gastric cancer, otherwise total gastrectomy should be avoided if possible. For single focal lesions, total gastrectomy may be preceded by preoperative drug therapy; combined organ resection should be performed to achieve R0 resection under the premise of ensuring surgical safety and adequate consideration of organ function. Lymph node metastasis rarely occurs in gastric GIST, and routine lymph node dissection is generally not recommended [19].
3.4 Small bowel GIST surgery
For GIST in the small intestine with a diameter of 2-3 cm, the margin distance can be reduced if the envelope is intact and there is no hemorrhage or necrosis. In the case of jejunal mesenchymal tumor, which is relatively small, end-to-end small bowel anastomosis after resection can be performed; sometimes the tumor becomes integrated with the mesenteric vessels, which is more common in the upper jejunum, and if resection is not possible, secondary surgery can be considered after drug treatment. 10%-15% of cases have lymph node metastasis, and the scope of lymph node dissection should be controlled as appropriate. The small intestine GIST may have lymph node metastasis, so it is appropriate to remove the surrounding lymph nodes.
3.5 Surgery for duodenal and rectal GIST
Surgery should be decided according to the size and location of the primary tumor, the degree of adhesion between the tumor and the surrounding organs, and the presence or absence of rupture of the tumor. For duodenal GIST, pancreaticoduodenectomy, local resection and intestinal wall repair, resection of duodenal 3-4 segments and proximal part of jejunum, and major gastrectomy are feasible. For rectal GIST, the surgical procedures are generally divided into local resection, anterior rectal resection and combined rectovaginal perineal radical surgery. In recent years, due to the use of molecularly targeted drugs, abdominal perineal radical surgery is decreasing, and the recommended indications are.
(1) Tumor does not shrink after drug treatment;
(2) Huge tumor, located below 5 cm from the anus, and cannot be separated from the rectal wall;
(3) Recurrent cases, which do not show significant improvement after first- and second-line drug treatment and affect defecation function.
3.6 Gastrointestinal GIST surgery
Surgery is still the preferred treatment modality, and the thoroughness of surgical treatment is closely related to the disease prognosis, and complete resection of the entire lesion is recommended [21.22]. In some patients, the tumor may adhere extensively to the surrounding tissues or spread, and sometimes biopsy or palliative surgery may be used to achieve a definitive diagnosis or tumor reduction with symptomatic relief [23].
3.7 Principles of endoscopic treatment of GIST
Due to the submucosal origin of GIST and the variety of growth patterns, endoscopic resection is feared to be difficult to perform radically, and the complications are high, so it is not routinely recommended.
Part III Principles of Molecular Targeted Drug Therapy
1.Preoperative treatment of GIST
1.1 The significance of preoperative treatment
At present, clinical trials on preoperative treatment of GIST are mostly small-scale retrospective studies or case reports. In the 2010 NCCN 2nd edition clinical practice guidelines for soft tissue sarcoma, the expert group suggested to rename “neoadjuvant therapy” as “preoperative therapy”, which was extended in the 2011 NCCN guidelines, and after discussion, this expert consensus agreed to adopt the latter term. After discussion, this expert consensus agreed to adopt the latter term. The main significance of preoperative treatment [16, 24, 25] is to reduce the tumor size and clinical stage; to reduce the scope of surgery, avoid unnecessary combined organ resection, reduce the risk of surgery, and increase the chance of radical resection; to protect the structure and function of important organs for tumors in special locations; and to reduce the risk of medical dissemination for patients with large tumors and high risk of intraoperative rupture and bleeding. For patients with huge tumors and high risk of intraoperative rupture and bleeding, it can reduce the possibility of medical dissemination.
1.2 Indications for preoperative treatment [16, 24, 25]
(i) Preoperative estimation is difficult to achieve R0 resection;
②Tumor size is huge (>10 cm), which is prone to bleeding and rupture during surgery and may cause medical dissemination;
③Tumors in special sites (e.g., gastroesophageal junction, duodenum, low rectum, etc.), surgery may easily damage the function of important organs;
④ Although the tumor can be resected, it is estimated that the surgical risk is high, and the postoperative recurrence rate and mortality rate are high; ⑤ It is estimated that a combined multi-organ resection is needed.
1.3 Preoperative treatment time, treatment dose and surgery timing selection
During drug treatment, the effect of treatment should be evaluated periodically (every 3 months), using the Choi criteria [26] or referring to the RECIST (Response Evaluation Criteriain Solid Tumors) criteria [27] is recommended. No unanimous consensus has been obtained by the expert committee regarding the timing of preoperative treatment. It is generally considered appropriate to give imatinib preoperative treatment for about 6 months to perform surgery [24]. Excessive prolongation of preoperative treatment may lead to secondary drug resistance. The recommended initial dose of imatinib for preoperative treatment is 400 mg/d [28]. For patients with tumor progression, the disease should be evaluated comprehensively, and those who are still operable (with the possibility of complete resection of the lesion) should discontinue the drug in time for early surgical intervention; for those who are not operable, second-line therapy can be used as in patients with recurrence/metastasis.
1.4 Preoperative drug discontinuation and postoperative treatment duration
It is recommended to stop the medication for about 1 week before surgery, and then consider surgery when the patient’s basic condition meets the requirements. After surgery, in principle, postoperative drug therapy should be performed as soon as the patient recovers gastrointestinal function and can tolerate drug therapy. For patients with R0 resection, the duration of postoperative drug maintenance can be referred to the standard of adjuvant therapy; for patients with palliative resection or metastasis or recurrence (whether or not R0 resection is achieved), postoperative treatment is similar to that for patients with recurrent/metastatic unoperated GIST.
2, GIST postoperative adjuvant therapy
2.1 Indications for adjuvant therapy
Patients at moderate to high risk of recurrence are currently recommended as an indication group for adjuvant therapy. The American Surgical Society (ASOCOG) Z9001 study [29] demonstrated that adjuvant treatment with imatinib for 1 year after complete resection of GIST with risk factors for recurrence significantly improved the recurrence-free survival of patients. Two domestic studies [30, 31] also confirmed the benefit of imatinib adjuvant therapy in patients with intermediate- to high-risk GIST.The ASOCOG Z9001 subgroup analysis [32], suggested that the benefit of adjuvant therapy varied among patients with different mutation types, and patients with c-kit exon 11 mutation and PDGFRA non-D842V could benefit from adjuvant therapy; meanwhile, there is no sufficient evidence that c-kit exon 11 mutation and PDGFRA non-D842V patients could benefit from adjuvant therapy. There is insufficient evidence to show whether c-kit exon 9 GISTs benefit from adjuvant therapy; while PDGFRA
This finding was repeated in the SSGXVIII/AIO study.
2.2 Dose and duration of adjuvant therapy
Based on the results of the ASOCOG Z9001 and SSGXVIII/AIO studies [29, 33], the currently recommended dose of adjuvant therapy with imatinib is 400 mg/d; the duration of treatment: for intermediate-risk patients, imatinib should be given for at least 1 year; for high-risk patients, adjuvant therapy should be given for 3 years. In the ASCOGZ9000 and Z9001 studies [29, 34], patients receiving imatinib adjuvant therapy for 1 year had a significantly higher rate of GIST recurrence after discontinuation, while the SSGXVIII/AIO study [33] showed that patients with high-risk GIST receiving imatinib adjuvant therapy for 3 years after surgery compared with 1 year further improved recurrence-free survival and overall survival. A domestic study [31] suggested that adjuvant treatment with imatinib for 3 years in patients with intermediate- and high-risk GIST may improve recurrence-free survival and overall survival at 3 years compared with patients who underwent surgery alone.
3. Treatment of metastatic recurrent/unresectable GIST
3.1 First-line treatment with imatinib
Imatinib is the first-line treatment for metastatic recurrent/unresectable GIST, and the recommended initial dose is 400 mg/d. The results of the B2222 trial [35] showed that imatinib was objectively effective in treating metastatic/recurrent GIST and significantly improved the median overall survival of patients. In the EORTC62005 study [36], a longer progression-free survival was achieved with imatinib 800 mg/d versus 400 mg/d; a high dose of imatinib is recommended for initial treatment, and given that most patients cannot tolerate imatinib 800 mg/d in domestic clinical practice, imatinib 600 mg/d can be given as initial treatment for national GIST patients with c-kit exon 9 mutations. metastatic recurrent/unresectable GIST, if imatinib therapy is effective, it should be continued until disease progression or intolerable toxicity occurs. The results of the BFR14 clinical study by the French Sarcoma Collaboration [37] suggest that interruption of imatinib treatment will result in recurrent disease and rapid tumor progression. Common adverse reactions to imatinib include edema, gastrointestinal reactions, leukopenia, anemia, rash, muscle cramps, and diarrhea [35, 36]; most adverse reactions are mild to moderate, occurring mostly in the first 8 weeks of dosing, are transient and self-limiting, and improve with symptomatic supportive therapy.
3.2 Treatment options after failure of standard imatinib dosing
If tumor progression occurs during imatinib treatment, the first step should be to confirm whether the patient has complied with medical advice, i.e., adhered to the drug at the correct dose; after excluding patient compliance factors, the following principles should be taken into account.
3.2.1 Limited progression
Focal progression is defined as the progression of some lesions during imatinib treatment, while others remain stable or even in partial remission. In the case of locally progressive GIST, surgery is recommended when complete resection of focal progressive lesions is possible, and postoperative treatment can be continued with the original dose of imatinib or increased dose. A small sample of clinical observations [38-40] suggested that patients with limited progression who underwent complete tumor resection and then continued imatinib achieved better disease-free progression and overall survival benefit. surgery is not recommended in cases of extensive GIST progression; when complete resection is not obtained, subsequent treatment should follow the principles of management of extensive GIST progression. For some patients with liver metastases from GIST who are unable to undergo surgery, arterial embolization with
radiofrequency ablation can also be considered as an adjuvant treatment modality [41, 42]; while patients with focal progression who are not suitable for local treatment can be treated with an increased dose of imatinib or given sunitinib.
3.2.2 Widespread progression
For those who develop extensive progression after standard dose of imatinib treatment, it is recommended to give an increased dose of imatinib or switch to sunitinib treatment.
① Imatinib dose increase: both the EORTC62005 and S0033 studies [36, 43] showed that increasing the imatinib dose to 800 mg in patients with extensively progressive GIST resulted in a re-clinical benefit in 1/3 of patients; the 2010 NCCN guidelines, 2nd edition, stated that a 400 mg Bid could be used. The increase in dose of imatinib is associated with a corresponding increase in adverse effects. Our GIST patients tolerate 600 mg/d imatinib better, and the efficacy is similar to that of the 800 mg/d dose reported abroad [44], so the priority increment of 600 mg/d is recommended for national GIST patients.
② Sunitinib treatment: The A6181004 study [45, 46] showed that the application of second-line treatment with sunitinib in patients who progressed or were intolerant to imatinib therapy remained effective and improved the time to disease progression and overall survival. The dose and mode of dosing, evidence from randomized controlled studies is lacking, with both 37.5 mg/d continuous and 50 mg/d (4/2) regimens as options. The major adverse reactions to sunitinib include anemia, granulocytopenia, thrombocytopenia, hand-foot syndrome, hypertension, oral mucositis, malaise, and hypothyroidism; most adverse reactions can be remitted and recovered with supportive symptomatic therapy or temporary discontinuation, but a few severe cases require discontinuation of sunitinib.
3.3 Maintenance therapy after treatment failure with imatinib and sunitinib
Patients with GIST who progress on both imatinib and sunitinib therapy are recommended to participate in clinical studies with new drugs or to consider maintenance therapy with drugs that were effective and well tolerated on previous therapy; other molecularly targeted drugs, such as sorafenib, may be considered [47], but more evidence from clinical studies is needed to support this.
4. Correlation of c-kit/PDGFRA gene mutations with the efficacy of molecularly targeted therapy
It is generally believed that c-kit/PDGFRA mutation types predict the efficacy of imatinib, with the best efficacy in those with c-kit exon 11 mutations [35]; PDGFRAD842V mutations may be resistant to primary imatinib versus sunitinib therapy [48]. The survival benefit of sunitinib for patients with primary c-kit exon 9 mutation and wild-type GIST is better than that of patients with c-kit exon 11 mutation; the efficacy of treating patients with secondary c-kit exon 13 and 14 mutations is better than that of secondary c-kit exon 17 and 18 mutations [49].
5. Monitoring of blood levels
If available, imatinib blood levels are recommended for the following patients.
(i) Patients progressing on first-line treatment with imatinib 400 mg;
②Patients with more severe adverse drug reactions;
A subgroup analysis of the B2222 study [50] confirmed that GIST patients with plasma imatinib concentrations below 1100 ng/ml had reduced clinical efficacy and rapid disease progression. Whether increasing the dose of treatment for patients with low imatinib blood concentrations can further improve the efficacy needs to be confirmed by clinical studies.
6. Judgment of drug efficacy
6.1 Definition of primary and secondary drug resistance
Primary resistance is defined as tumor progression within 3-6 months of first-line treatment with imatinib; the recommended observation period is 3 months if assessed by chio criteria. Secondary resistance is defined as tumor progression after initial treatment with imatinib or sunitinib to achieve tumor remission or stabilization, followed by prolonged treatment.
6.2 Modified Choi Efficacy Assessment Criteria
GIST targeted therapy is effective in those with early changes in tissue composition, often with necrosis, hemorrhage, cystic degeneration and mucinous changes as the main manifestations, and sometimes the volume reduction can be insignificant or even increase. The RECIST criterion, which was previously used to evaluate the efficacy of cytotoxic drugs, only takes into account volume changes and has obvious shortcomings; Choi et al. proposed a new criterion (see Table 91-2 for details) that combines the Hu values of long diameter and CT [26], and some studies showed that its efficacy evaluation ability is better than the RECIST criterion. This consensus suggests that for those tumors with insignificant or even enlarged volume reduction in the early stage of treatment, the Hu value of CT should be measured additionally and evaluated according to the Choi standard.
6.3 CT scan and measurement specifications
① Scanning range: It should be from the top of the diaphragm to the pelvic floor, including the whole abdominal and pelvic area.
② Scanning parameters: fasting from 12 hours before the examination; intravenous injection of non-ionic contrast agent at a rate of 3-4 mL/s, single-row spiral CT at 30 seconds and 60 seconds, and multi-row spiral CT at 20 seconds, 40 seconds and 60 seconds after injection; thin layer scanning with a layer thickness of ≤5 mm is required.
③Length diameter and CT value measurement methods: axial images to measure the maximum diameter of the tumor; enhanced venous phase, the overall CT value of the tumor (Hu) was obtained at the maximum level of the tumor using the curve edge tracing method. In principle, enhancement scan is required. If contraindicated, it is recommended to switch to MRI scan, which can detect lesions more sensitively than CT plain scan and can find early histological changes such as cystic and mucinous lesions.
6.4 Application of PET-CT
PET-CT scan combines molecular imaging with morphological imaging and is currently the most sensitive means of assessing the efficacy of molecularly targeted drugs in the treatment of GIST, which is of great value and should be actively applied when available; however, because the machine and equipment are not yet popular and expensive, it has not yet been clearly written into international guidelines and is not used as a routine tool for the time being.
6.5 Application of MRI
MRI has the characteristics of high soft tissue resolution and sensitive tissue water content, and is another imaging tool that can provide quantitative functional indicators in addition to PET-CT; magnetic resonance diffusion-weighted imaging (DW-MRI) is one of the more mature techniques, but its exact clinical significance needs to be further confirmed.
7/Follow-up principles
For all GIST patients, a complete case file should be established for systematic follow-up.
7.1 Patients with postoperative follow-up
The most common sites of metastasis after GIST surgery are the peritoneum and the liver, so enhanced CT or MRI scans of the abdomen and pelvis are recommended as routine follow-up items.
(i) For intermediate- and high-risk patients, CT or MRI should be performed every 3 months for 3 years, and then every 6 months until 5 years;
(ii) For low-risk patients, CT or MRI should be performed every 6 months for 5 years;
(iii) Because of the relatively low incidence of pulmonary and skeletal metastases, at least one chest X-ray per year is recommended, and an ECT bone scan is recommended in the presence of associated symptoms.
7.2 Patients with metastatic recurrence/unresectable or preoperative treatment
①Enhanced CT must be performed before treatment as a basis for baseline and efficacy assessment;
②After starting treatment, follow-up should be performed at least every 3 months to review the enhanced CT or MRI; if treatment decisions are involved, the frequency of follow-up can be increased appropriately;
③ Close monitoring at the beginning of treatment (first 3 months) is very important, and PET-CT scan can be done if necessary to confirm the tumor response to treatment;
④If necessary, blood concentration changes should be monitored to guide clinical treatment.