<p>Even though we are in an era of targeted therapies for gastrointestinal stromal tumors (GIST), surgery remains the only curative option. For surgery to be successful, many patients need to receive neoadjuvant therapy. However, the role of adjuvant therapy and its effect on the long-term effectiveness of surgery remain to be fully elucidated.</p>

There can be diagnostic dilemmas with small gastric subepithelial lesions, usually those with a diameter of less than 3 cm that can be hard to resolve without operating. The problem is that, many times, there is not sufficient tissue from fine-needle aspiration or endoscopic biopsies to establish a diagnosis. Since the results may be indeterminate, I need to decide whether to watch and repeat a scan in 3 to 6 months or remove the tumor laparoscopically. For tumors with a diameter of less than 2 cm, guidelines suggest to watch, but for those that are larger, I do not want to potentially miss a GIST diagnosis.

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For patients who have a single tumor without metastasis, I always hope to do surgery. Sometimes, I can operate immediately, but other times, I have to use neoadjuvant therapy. Imatinib is the only TKI with US Food and Drug Administration (FDA) approval for patients with KIT-positive unresectable or metastatic GIST in the neoadjuvant setting. I try to shrink the tumor if I think that it will drastically alter the operation to remove it, especially for patients with tumors in challenging locations such as the gastroesophageal junction, the second portion of the duodenum, or the rectum. I also use it for very large tumors that look like they would require the partial removal of other organs or cause a lot of bleeding. The other TKIs that are FDA approved to treat GIST in later lines of therapy have not been well tested in the neoadjuvant setting and are not indicated in this setting, but their use could be considered. For patients with metastatic GIST in whom we sometimes consider surgery, I use the term “preoperative in the metastatic setting” rather than “neoadjuvant.”

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In terms of resection, there are different ways that a partial gastrectomy can be performed. Laparotomy is done for very large tumors, typically those with a diameter of greater than 8 cm. It is also sometimes done for tumors located near the gastroesophageal junction. Surgery can also be performed laparoscopically, robotically, or endoscopically. Some people do endoscopic full-thickness resections, but I generally do not prefer doing a full-thickness endoscopic resection from the stomach and clipping it back together. In contrast, small tumors can often be removed laparoscopically very quickly and with very low risk because staplers are used to staple the incised edges of the stomach.

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In the adjuvant setting, imatinib is generally not curative, even in patients who have only microscopic disease after tumor resection. In the large, randomized, phase 3 ACOSOG Z9001 trial comparing adjuvant imatinib with placebo in patients with GIST that have a diameter of at least 3 cm, based on the relapse-free survival in the placebo group, approximately 75% of patients were cured from surgery alone. Some patients treated with 1 year of adjuvant imatinib therapy will eventually see their GIST recur once the drug is stopped, and it became clear from the trial that just 1 year of adjuvant therapy did not change the rate of recurrence in the long run. A controversy right now is whether patients with high-risk tumors should discontinue adjuvant therapy. In the single-arm phase 2 PERSIST-5 trial, 91 patients were treated with adjuvant imatinib for 5 years. Only 1 patient had a recurrence while receiving imatinib, and it was associated with a PDGFRA D842V mutation, which is imatinib resistant. However, it is unclear whether there is an overall survival or disease-specific survival advantage with adjuvant imatinib.

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Some patients have germline mutations, which can include mutations in the SDH or NF1 genes, and their GIST can act much differently than the GIST of other patients, as, much of the time, their GIST does not respond to TKIs. Due to this, surgery plays a larger role for these patients, and the main thing is trying to figure out what the extent of surgery should be and when to intervene. Since SDH-altered GIST tend to be indolent, we often operate on them in the metastatic setting.