In 2010, the Chinese Society of Clinical Oncology (CSCO) established the Gastrointestinal Mesenchymal Stromal Tumor Expert Committee, and established the GIST diagnosis and treatment consensus in China, and wrote the first GIST China Consensus (2011 edition), which has been updated once a year since then. The consensus is updated annually. Here, the author discusses the new consensus recommendations for GIST in the 2014 edition of the NCCN guidelines, as well as the comparison with the previous edition and our expert consensus, the main updates and controversies.
Disease assessment and ancillary tests
All GIST patients must be evaluated by a multidisciplinary team of experienced sarcoma experts before starting treatment, and their risk must be assessed before adopting the appropriate treatment strategy. The new NCCN guidelines emphasize the difficulty and inadequacy of predicting the biological behavior (malignant potential) of GIST based on only two pathologic features, tumor size and nuclear schwannomegaly, and require that the site of tumorigenesis be included as an indicator of risk assessment.
The new NCCN guidelines suggest that most gastric GISTs are biologically well behaved, relatively slow-growing, and mostly benign below 2 cm; whereas small intestinal GISTs are biologically more aggressive, and colorectal GISTs mostly occur in the rectum, also with aggressive biological behavior, and are prone to recurrence and metastasis even if the tumor is <2 cm.
Although some mutational features of the C-KIT and PDGFRA genes correlate with tumor phenotype, mutations in the C-KIT and PDGFRA genes do not correlate significantly with the biological behavior of GIST, which occurs in both highly malignant GIST and relatively benign gastric GIST <2 cm. Similarly, PDGFRA mutations do not predict the biological behavior of GIST.
Adjunctive testing includes pelvic and abdominal enhanced CT and/or MRI, chest imaging, and endoscopic ultrasound, with or without endoscopy depending on clinical indications and surgical needs. The previous NCCN guidelines did not consider genetic testing to be a necessary step in the diagnosis of GIST, and only tested for C-KIT and PDGFRA gene mutations when postoperative targeted therapy or preoperative neoadjuvant therapy was considered to exclude patients with primary drug resistance and to guide drug dose selection.
In contrast, the new NCCN guidelines strongly recommend testing for C-KIT and PDGFRA gene mutations prior to treatment, and for wild-type patients lacking C-KIT and PDGFRA gene mutations, further tests such as immunohistochemical staining for the presence of succinate dehydrogenase (SDH) B protein expression, and SDH gene loss-of-function mutation testing should be given. With the publication of research results, there is a recent trend to replace wild-type GIST with SDH-deficient GIST, and DOG1 immunostaining may be useful for diagnosing GISTs that are difficult to diagnose with CD117 staining and C-KIT/PDGFRA mutation testing.
Tumor Biopsy
For most primary GISTs that can be completely resected, routine biopsy or puncture is not recommended prior to surgery. However, if targeted therapy needs to be given preoperatively, a pathological diagnosis is required and genetic testing is recommended. As for biopsy modalities, the NCCN guidelines always recommend ultrasound endoscopic fine-needle aspiration biopsy (EUS-FNA) based on the fact that GIST is a soft and brittle tumor. However, the tissue obtained by EUS-FNA, although sufficient for HE and immunohistochemical staining, may not meet the requirements for genetic testing.
The national expert consensus states that GIST of the middle and lower rectum can be biopsied by coarse needle aspiration through the rectal wall with a very high positive rate and sufficient harvested tissue for genetic testing. Percutaneous aspiration carries the risk of needle tract implantation and tumor rupture leading to abdominal dissemination and is only indicated for GIST with suspected metastasis.
Limitations of Surgical Treatment of GIST
Surgical treatment of GIST
The NCCN guidelines summarize the principles of surgery for GIST succinctly, which is to try to ensure complete resection of the tumor and negative margins. In the past, it was generally believed that benign gastric GISTs <2 cm were more common and could be treated without treatment, with only close follow-up. The new guidelines emphasize that if a gastric GIST <2 cm is confirmed by biopsy (fine-needle aspiration is recommended) and shows high-risk signs on ultrasound endoscopy (irregular tumor margins, uneven internal echogenicity, necrosis, localized cystic or solid echogenicity), surgical resection should be considered, with follow-up pelvic and abdominal enhanced CT and/or MRl scans every 3-6 months for 3-5 years after surgery and annually thereafter. GIST without the above ultrasound endoscopic high-risk signs may be followed up with ultrasound endoscopy at intervals of 6 to 12 months without surgery for the time being.
Surgical treatment of primary resectable GIST
Our expert consensus recommends that at least every 3
The NCCN guidelines suggest that when two consecutive CT examinations reveal that the tumor is no longer retracting, the treatment has reached its maximum effect, which is the best time for surgery; however, it also points out that not all patients need to wait until the treatment has reached its maximum effect before undergoing surgery. Surgeon’s judgment is important, as surgery can be performed when complete resection of the tumor is expected without affecting organ function, as delaying surgery may result in tumor progression due to drug resistance during two CT evaluations in some patients.
The NCCN guidelines recommend that laparoscopic surgery for GIST should be performed in an experienced center, and appropriate cases should be selected according to the site of tumor growth, such as tumors growing in the greater curvature or anterior wall of the stomach, jejunal or ileal GIST. GIST is most suitable for laparoscopic resection, while GIST in the cardia, posterior wall of the lesser curvature of the gastric body and sinus are relatively inappropriate for laparoscopic resection.
Surgical treatment of unresectable or metastatic GIST
Imatinib-targeted therapy is the treatment of choice for unresectable or metastatic GIST. In recent years, the role of surgery in the treatment of advanced GIST has been re-evaluated. Both domestic and foreign reports have shown that patients with well-controlled or limited tumor progression under the premise of targeted drug therapy have better safety and mid- and long-term postoperative efficacy of surgical treatment, while patients with extensive progression fail to benefit from surgery.
Therefore, both the NCCN guidelines and our expert consensus recommend screening patients with advanced disease for surgical intervention.
The new NCCN guidelines state that the following situations are suitable for surgical treatment.
①Newly emerged imatinib-resistant localized lesions that can be surgically resected for drug-resistant lesions.
Patients with locally progressive GIST should receive the original dose of imatinib regardless of whether they have received surgery, radiofrequency ablation, embolization or palliative radiotherapy (for rare bone metastases only), as these patients are often incompletely resected and have a high incidence of postoperative complications. of imatinib.
The new NCCN guidelines emphasize the importance of discontinuing the drug before surgery and restarting imatinib therapy as soon as the patient is physically able to do so. If treated with other tyrosine kinase inhibitors (TKI) such as sunitinib or regorafenib, at least 1 week of drug discontinuation is required before undergoing surgery, and the timing of post-operative re-treatment is relatively more conservative, requiring clinical judgment that the patient has fully recovered before receiving treatment again.
GIST Targeted Therapy
Imatinib Targeted Therapy
The EORTC62005 and S0033/CALGB150105 studies found that metastatic or unresectable GIST treated with 400 mg/d and 800 mg/d imatinib had similar efficiency and overall survival (OS) rates, but the higher doses had greater side effects. Therefore, an initial recommended dose of 400 mg/d is generally advocated, while for patients with C-KIT exon 9 mutations, some foreign scholars advocate that the initial therapeutic dose of imatinib should be 800 mg/d.
In view of the fact that most patients cannot tolerate imatinib 800 mg/d in domestic clinical practice, imatinib 600 mg/d can be given as initial treatment for GIST patients with C-KIT exon 9 mutation in China.
Preoperative Imatinib Treatment
Surgery is the treatment of choice for resectable GIST, but preoperative imatinib is recommended for patients with high surgical risk and possible surgical complications. Pre-operative treatment can lead to tumor shrinkage and reduce the risk of surgery. Imatinib is usually given at a dose of 400 mg/d, or 600 mg/d for patients with C-KIT exon 9 mutations, and close monitoring is essential as some patients may progress rapidly to unresectable in a short period of time.
The duration of preoperative treatment is not known, but it is generally considered best to continue until the patient achieves maximum efficacy, i.e., until the tumor no longer shrinks on two CT assessments, which is usually considered to be about 6 to 12 months. Of course, in case of bleeding or symptoms, early surgical intervention is required.
The results of several clinical studies confirm the safety and efficacy of preoperative imatinib treatment, however, in all patients who received preoperative imatinib treatment and obtained tumor resection, the survival benefit was not significant with subsequent 2-year postoperative imatinib treatment. Therefore the need for preoperative imatinib treatment for resectable, locally advanced or recurrent GIST needs to be assessed on an individual basis.
Adjuvant Imatinib Treatment
Complete first-time resection of the primary tumor is possible in 85% of patients with GIST; however, even with complete surgical resection, 50% of patients may develop recurrence or metastasis after surgery, with a 5-year OS rate of approximately 50%. The median time to recurrence after surgery for high-risk GIST is approximately 2 years.
Patients with an intermediate to high risk of recurrence are currently recommended as a suitable population for adjuvant therapy. The benefit of adjuvant therapy varies among patients with different mutation types; patients with C-KIT exon 11 mutations and PDGFRA non-D842V mutations may benefit from adjuvant therapy; patients with C-KIT exon 9 mutations are recommended to be treated directly with 600 mg/d, while wild-type GISTs need to be further investigated for benefit from adjuvant therapy; and patients with PDGFRA D842V mutation GIST patients failed to benefit from adjuvant therapy.
The 2012 edition of the NCCN consensus recommends 3 years of postoperative adjuvant therapy for high-risk patients, but the optimal duration of treatment after 3 years is unclear. The new NCCN guidelines recommend that treatment should be continued for as long as there is clinical benefit (effective or SD) for patients with GIST treated with TKI. It also states that if TKI therapy improves symptoms in GIST patients, TKI lifelong therapy can be a key component of optimal supportive care for patients.
And if targeted therapy is interrupted briefly for 1 to 2 weeks due to medical necessity, it will not adversely affect the patient’s disease control or other outcomes.
Treatment after Imatinib Resistance
Patients with GIST who develop disease progression (localized progression or extensive metastases but good behavioral status) after receiving standard doses of imatinib may be treated by increasing the imatinib dose to 800 mg/d or by switching to sunitinib. 33% of patients still achieved disease remission.
Since the majority of patients with locally progressive GIST cannot be effectively controlled with imatinib plus dose, second-line sunitinib therapy is usually recommended. regorafenib is the third-line treatment after failure of imatinib and sunitinib therapy. And after third-line regorafenib therapy no longer benefits, guidelines recommend that sorafenib, dasatinib, or nilotinib may be treatment options for patients, although there is limited evidence to support this.
After all current targeted therapeutic drug therapy has failed to work for the patient, restarting a tolerable and previously effective targeted drug therapy may provide remission of the patient’s symptoms. A recent randomized study confirmed that patients with GIST who failed imatinib and sunitinib therapy and restarted imatinib therapy had significantly higher PFS rates and disease control rates (DCR). However, the duration of survival benefit for patients was shorter due to the continued progression of drug-resistant lesions. After failure of all of the above available targeted therapies, patients are advised to enter clinical trials if suitable clinical trials are available.