Treatment for Patients With Recurrent Gastrointestinal Stromal Tumors
For patients already receiving imatinib, the recurrence of gastrointestinal stromal tumors (GIST) may reflect disease persistence or drug resistance. In the case of the latter, a number of known resistance-conferring mutations are being targeted by new and emerging therapies. Clinical trials are also investigating novel treatments and combination strategies.
What are the best practices for detecting and treating GIST recurrence?
Professor of Medicine
“Our practice is to have a very low threshold for performing biopsies to confirm the recurrence. Even intra-abdominal masses may not always be recurrences of GIST.”
At our institution, patients who have already undergone surgery to remove primary GIST are followed for a period of time with contrast computed tomography scans of the abdomen and pelvis, chest x-rays, and routine laboratory testing. Thyroid-stimulating hormone levels are tested if the patient is taking an agent that causes hypothyroidism or is having symptoms of hypothyroidism. These tests are performed every 3 months for the first 2 years, every 4 months for the next 2 years, every 6 months for the following year, and then annually after 5 years. For those with metastatic disease who are on therapy, the same imaging approach is taken, but tests are performed every 2 months initially. The interval is increased to 3 months, and, in some cases, 6 months if the patient demonstrates a robust response to therapy and a low volume of disease. Some patients who have been on imatinib for widespread metastatic disease in excess of 10 years may be imaged only every 6 months.
Circulating tumor DNA is assessed at the time of progression to determine whether the secondary resistance driver mutation is exon 13 or exon 17. The exon 13 mutation is more sensitive to sunitinib than to any other agent, but exon 17 is not responsive to sunitinib. In this case, regorafenib appears to have greater activity and will be used.
Patterns of metastases are quite similar in the current treatment era as in the past, with primarily the liver and peritoneal cavities involved. As patients live longer and have wider-spread metastases, we do see bone metastases, brain metastases, and, occasionally, lung metastases; however, these are rare. Our practice is to have a very low threshold for performing biopsies to confirm the recurrence, and, if there is a suspicion of GIST present in the bone or lungs, a core needle biopsy should be performed to determine whether those lesions represent GIST or another entity. Even intra-abdominal masses may not always be recurrences of GIST; in a study we conducted, desmoid tumors were identified in a number of patients with GIST. Metastases to the lungs are also biopsied, and many of these patients have been found to have sarcoidosis instead of metastatic GIST. The driver(s) of the association between GIST and desmoid tumors or GIST and sarcoidosis are not known, but these entities should be on the radar.
Professor of Medicine
“Any GIST recurrence during or shortly after adjuvant therapy should be regarded as resistant disease requiring second-line therapy.”
Identifying the specific tumor mutation driver is critical to optimizing the treatment of patients with GIST, whether in the adjuvant treatment setting or the metastatic setting. Any GIST recurrence during or shortly after adjuvant therapy should be regarded as resistant disease requiring second-line therapy. However, if the patient has metastatic disease that develops 1 or 2 years after completion of the adjuvant therapy, and it is KIT exon 11–mutant GIST, then data indicate that the recurrence should be regarded as persistence rather than resistance, as these patients can be treated again with imatinib and do quite well.
The optimal role for cytoreductive surgery in recurrent KIT exon 11–mutant GIST remains unclear. In my view, cytoreductive surgery should be regarded as an investment toward a long-term future, and the question that should be answered in every case is: Will be the patient be better off in 5 or 10 years by performing the surgery today, or would there be no difference as compared with targeted therapy? The best candidates for cytoreductive surgery are patients with metastatic GIST whose disease is stable or responsive to imatinib and who have easily resectable tumors that can be entirely removed. In these cases, cytoreductive surgery can offer a technically feasible way to improve an individual’s chances for long-term survival. Surgery, however, carries a high risk for incomplete resection and complications. Therefore, patient selection through multidisciplinary communications among radiology, oncology, and surgical oncology is critical to determine not only which patients should receive surgery but also—perhaps more importantly—who should not receive surgery.
“Patients with recurrent GIST should also be offered the option of participating in clinical trials, such as trials of immunotherapy. The field is still in its early days as relates to immunotherapy for GIST, but we are hopeful that this will be another tool in our weaponry.”
Best practices for detecting and treating GIST recurrence begin at the outset of treatment with accurate risk stratification, based on the size and location of the tumor, the number of mitoses per high power field, and other factors such as tumor rupture. A patient who has an intermediate- or high-risk GIST should be on imatinib for at least 3 years after surgery, even if the tumor was completely resected, and many would argue for a longer duration. Metastatic disease, either in the liver or elsewhere in the abdomen and pelvis, is often diagnosed when there is recurrence in a patient already receiving imatinib. In these cases, one would use sunitinib or regorafenib. Contemporary guidelines have listed other agents that might be used in this setting, such as pazopanib, dasatinib, and cabozantinib; nilotinib might be used in the absence of an exon 9 mutation.
Patients with recurrent GIST should also be offered the option of participating in clinical trials, such as trials of immunotherapy. The field is still in its early days as relates to immunotherapy for GIST, but we are hopeful that this will be another tool in our weaponry.
I agree that cytoreductive surgery for patients with recurrent and/or multifocal metastatic disease should be discussed among a multidisciplinary sarcoma tumor board. Surgery might be considered, for instance, in a well-controlled patient who has multiple tumors in the abdomen that are considered cases of clonal outgrowth; radiation or some other local control option such as ablation might also be considered.
Chaudhry UI, DeMatteo RP. Advances in the surgical management of gastrointestinal stromal tumor. Adv Surg. 2011;45:197-209. doi:10.1016/j.yasu.2011.03.018
Fairweather M, Balachandran VP, Li GZ, et al. Cytoreductive surgery for metastatic gastrointestinal stromal tumors treated with tyrosine kinase inhibitors: a 2-institutional analysis. Ann Surg. 2018;268(2):296-302. doi:10.1097/SLA.0000000000002281
Florou V, Trent JC, Wilky BA. Precision medicine in gastrointestinal stromal tumors. Discov Med. 2019;28(155):267-276.
Gronchi A, Bonvalot S, Poveda Velasco A, et al. Quality of surgery and outcome in localized gastrointestinal stromal tumors treated within an international intergroup randomized clinical trial of adjuvant imatinib. JAMA Surg. 2020;155(6):e200397. doi:10.1001/jamasurg.2020.0397
Keung EZ, Fairweather M, Raut CP. The role of surgery in metastatic gastrointestinal stromal tumors. Curr Treat Options Oncol. 2016;17(2):8. doi:10.1007/s11864-015-0384-y
Parab TM, DeRogatis MJ, Boaz AM, et al. Gastrointestinal stromal tumors: a comprehensive review. J Gastrointest Oncol. 2019;10(1):144-154. doi:10.21037/jgo.2018.08.20
Raut CP, Espat NJ, Maki RG, et al. Efficacy and tolerability of 5-year adjuvant imatinib treatment for patients with resected intermediate- or high-risk primary gastrointestinal stromal tumor: the PERSIST-5 clinical trial. JAMA Oncol. 2018;4(12):e184060. doi:10.1001/jamaoncol.2018.4060