Gastrointestinal stromal tumor (GIST) is a group of tumors that originate from cajal mesenchymal cells in the gastrointestinal tract. The introduction of imatinib, a tyrosine kinase inhibitor (TKI), has revolutionized the treatment paradigm of GIST, and the NCCN, ESMO, and the Chinese GIST Expert Consensus all stipulate that adjuvant targeted therapy should be taken for 1 to 3 years after surgery for intermediate to high-risk GIST.
In fact, with the publication of new clinical evidence, the optimal timing of postoperative adjuvant therapy for high-risk recurrence cases has not been determined. In addition, with the publication of literature on the relationship between genetic testing and prognosis in Z9001, scholars prefer to use genetic testing methods to develop individualized adjuvant treatment regimens for GIST patients after complete resection: cases with exon 9 mutations require higher doses in adjuvant therapy to benefit; cases with exon 11 mutations can significantly reduce the risk of recurrence or metastasis with adjuvant therapy.
With the clinical application of imatinib for more than 10 years, the number of recurrent metastasis cases is gradually increasing, and it is an urgent clinical problem to develop a reasonable treatment strategy for this group of patients, so that they can receive more timely and reasonable treatment, improve their quality of life and prolong their survival. Targeted therapy for recurrent metastatic GIST resected by surgery.
1. First-line treatment with imatinib.
An open multicenter phase II clinical study (B2222 trial) in 2002 demonstrated for the first time that the standard therapeutic dose of imatinib 400 mg/d could result in a GIST disease control rate of 83.7% [1]; the median survival rate reached 57 months and the 9-year survival rate was 35% [2]. The results of a randomized controlled phase III clinical study in the French Sarcoma Group (BFR14 trial) demonstrated that patients with metastatic GIST treated with imatinib achieved a longer median progression-free survival time with continuous dosing compared with the interrupted treatment group (P<0.05< span="">) [3].
It is generally accepted that imatinib 400 mg/d treatment should be preferred for metastatic recurrent GIST cases that have not received previous TKI treatment; for patients who have received previous TKI treatment, genetic testing is first recommended to clarify the type of mutation, and for patients with exon 9 mutations, imatinib 800 mg/d treatment is recommended.
The EU-AUS study in Europe included 946 patients with inoperable or metastatic GIST, randomized into the imatinib 400 mg/d and 800 mg/d groups, and showed that those with exon 9 mutations receiving the 800 mg/d treatment dose were able to achieve longer progression-free survival and high overall survival rates. According to the data from Peking University Cancer Hospital and our clinical practice, it is difficult for the national population to tolerate a dose intensity of 800 mg/d, and a 600 mg/d dose addition is generally recommended.
2. Second-line treatment with sunitinib.
In 2006, Demetri et al. reported the results of an international multicenter randomized controlled study of GIST in which sunitinib failed in second-line treatment with imatinib: the sunitinib treatment group significantly improved the median time to progression of patients compared to the placebo group (27.3 weeks and 6.4 weeks); the overall survival time of patients in the treatment group was also better than that of the control group (73.9 weeks and 35.7 weeks). The latest single-center study in China showed that 45 patients treated with sunitinib after imatinib resistance had complete remission, partial remission and disease stabilization rates of 15.6%, 8.9% and 46.7%, respectively, after 3 months of treatment; multifactorial analysis showed that progression-free survival and overall survival rates were better in patients with exon 9 mutation and wild type than those with exon 11 mutation (P<0.05< span="">).
In another domestic study of 48 imatinib-resistant patients treated with sunitinib, the efficacy of two dosing regimens, 50 mg/d for 4 weeks with a 2-week stop and 37.5 mg/d continuous oral dosing, was analyzed, and the results showed that patients with exon 9 mutations had better outcomes than those with exon 11 mutations, and that the sunitinib 37.5 mg/d continuous oral regimen was safe and reliable. The place of surgery in recurrent metastatic GIST
In recent years, targeted therapy has replaced surgery as the main treatment for advanced GIST. However, the complete remission rate of targeted therapy is still unsatisfactory, and some patients may develop primary or secondary resistance, necessitating a re-evaluation of the status of surgery in the treatment of advanced GIST. A meta-analysis has shown that surgical resection for those with progressive disease (PD) after targeted therapy for advanced GIST may still prolong survival.
Preoperative application of TKI in patients with recurrent or metastatic GIST can significantly reduce tumor volume, which is positively correlated with the efficacy of treatment and surgical resection rate. Early surgical intervention is advisable for those who are effective, and complete resection is difficult once PD appears. An et al. retrospectively analyzed 249 cases of progressive GIST, 35 of which underwent tumor reduction (resected lesions greater than or equal to 75%), and the follow-up results showed that tumor reduction before the application of imatinib did not improve the prognosis of patients. Therefore, imatinib should still be used as first-line treatment for locally progressive GIST.
The RTOG S0132 study showed that patients with GIST treated with neoadjuvant imatinib had a postoperative complication rate of less than 10%; with a median follow-up of 5.1 years, patients with GIST who achieved SD or partial remission (PR) with imatinib treatment had a median progression-free survival (PFS) of approximately 3 years and an overall survival (OS) of more than 5 years after reoperation plus imatinib adjuvant therapy [10]. The COMVIA study, on the other hand, showed that in patients with recurrent metastatic GIST, surgery plus postoperative imatinib treatment resulted in significantly longer relapse-free survival than imatinib treatment alone, suggesting that the efficacy of targeted therapy combined with surgery is superior to that of those treated with targeted therapy alone.
Liver metastases are the most common type of recurrent metastatic GIST, and in cases where TKI therapy is not available (economic reasons or allergy, etc.), surgical treatment of GIST liver metastases is significantly better than non-surgical treatment, although there are no direct controlled studies to confirm that surgical treatment is better than non-surgical treatment, with reference to previous studies on gastrointestinal sarcomas. Studies have shown that surgical resection of liver metastases from sarcomas including GIST is the best treatment, while radiofrequency treatment has a higher rate of local recurrence and intrahepatic metastases than surgical resectors.
For liver metastases from GIST without surgical access, Sloan Kettering’s data over the past 20 years suggest that only 26% of GIST patients with liver metastases could be surgically resected before the widespread use of TKI. The rates of complete remission, partial remission and disease stabilization were 5.8%, 50.7% and 32.4%, respectively. III. Surgery combined with targeted therapy
For relapsed metastatic GIST, targeted therapy is always the first choice and basis of treatment and should be taken continuously. Surgical treatment only plays a role as adjuvant therapy. A subgroup analysis of the BFR14 study showed that locally advanced GIST treated with preoperative imatinib was treated with surgery in 36% of cases, but there was no significant difference in OS and PFS compared to patients who did not undergo surgery. A domestic single-center retrospective analysis showed that for patients with surgically resectable locally advanced GIST, preoperative imatinib resulted in a disease control rate of 93.3%, an R0 resection rate of 86.7%, and a 5-year overall survival rate of 83%. It can be a potentially advantageous treatment modality for primary high-risk resectable GIST.
It is safe and reliable to select cases with good systemic status and satisfactory disease control with TKI therapy or only local progression for surgical intervention. The principle of surgery is to achieve R0 or R1 whenever possible. based on our center’s experience, patients taking imatinib should stop taking the drug for 1 week before surgery, and patients taking sunitinib should stop taking the drug for 2 weeks to ensure surgical safety and reduce the risk of intraoperative bleeding and postoperative anastomotic fistula. tKI combined with surgical resection is currently the best treatment modality for recurrent metastatic GIST, which can improve patient survival. It is difficult to achieve R0 or R1 resection in recurrent metastatic GIST cases, and in principle, all cases should be continued on medication postoperatively. There is no clear rule on when to start the medication, European and American doctors recommend starting the medication as early as possible, and domestic experts generally recommend starting the medication 2~4 weeks after surgery. Targeted therapy
A recent randomized, placebo-controlled phase III clinical study of patients with metastatic recurrent GIST who failed imatinib and sunitinib therapy and could not be surgically resected, randomized cases into 41 cases in the group receiving imatinib 400 mg/d again and 40 cases in the placebo group, with a median follow-up time of 5.2 months; as a result, the median PFS time for patients receiving imatinib treatment was 1.8 months, compared to placebo group was only 0.9 months (P=0.005); 37 patients in the placebo group crossed over to the imatinib group.
The most common grade 3 adverse effect in patients in the imatinib-treated group was anemia (29% versus 8%). The authors concluded that although patients with relapsed metastatic GIST have developed resistance to standard complexine kinase inhibitors, clones sensitive to complexine inhibitors remain within the lesion, and therefore suggested that in this group of patients, continued use of imatinib may slow the rate of disease progression.
An international multicenter, randomized, placebo-controlled phase III clinical study (GRID) of patients with metastatic recurrent GIST who failed treatment with imatinib and sunitinib was divided into those receiving a multikinase inhibitor (regorafenib group) (199 patients) and those receiving placebo (66 patients); as a result, the median PFS was 4.8 months in the treatment group and only 0.9 months in the control group (P <0.0001); 85 patients who received placebo progressed crossed over to the regorafenib group; the most common grade 3 adverse reactions in the treatment group were hypertension (23%), hand-foot skin reactions (20%), and diarrhea (5%).
In the latest published multicenter phase II clinical study, 25 GIST patients who failed imatinib and sunitinib treatment received pazopanib (pazopanib) 800 mg/d orally, and 48% reached SD with a median PFS time of 1.9 months and median overall survival of 10.7 months; the patients were well tolerated overall with no expected adverse effects.
In summary, targeted therapy should be preferred in cases of relapsed metastatic GIST, and genetic testing should be done to clarify the mutation type in cases previously treated with TKI. Those with exon 9 mutations should be treated with high-dose imatinib, and those with clear imatinib resistance should be treated with sunitinib. Surgical intervention should only play an adjuvant role, and surgery can be considered for cases with satisfactory disease control with targeted therapy or only local progression, and the principle of surgery is to try to achieve R0 or R1 resection. Regorafenib and pazopanib may still be effective in patients with GIST who have failed standard therapy.