Chapter 25. Perspective on Gastrointestinal Stromal Tumors

In the accompanying chapter, Dr Raut provides an overview of gastrointestinal stromal tumor (GIST). Clearly, the development of tyrosine kinase inhibitors for GIST is one of the most remarkable achievements to date for any solid tumor. Patients with metastatic GIST historically had a median survival of 12 months, but it is now 5 years.1,2 The paradigm of targeted molecular therapy has been subsequently expanded to lung adenocarcinoma with epidermal growth factor receptor (EGFR) inhibitors, renal carcinoma with vascular endothelial growth factor receptor (VEGFR) inhibitors, and most recently melanoma with B-Raf inhibitors. Although GIST is an uncommon tumor, lessons from “the GIST story” will have relevance to the multimodality therapy of these more common tumors and other cancers for which targeted therapy is developed.

Despite the advances in molecular therapy, it is critical to realize that surgery remains the only potentially curative treatment for GISTs. There are no data to support chronic therapy with molecular agents instead of surgical removal in patients who are otherwise healthy and expected otherwise to have prolonged survival. Thus, a thorough understanding of the surgical principles for GIST is essential.

There are a variety of surgical issues in GIST that deserve emphasis. First, it is important to handle GISTs gently, as they are often soft and prone to tumor rupture. They may become even more friable after response to neoadjuvant therapy. During laparoscopic resections, specimens should be placed into a plastic bag prior to removal from the abdominal cavity. Large GISTs tend to have extensive arterial and venous collaterals. Thus, careful dissection is necessary to minimize the chance of significant blood loss. While GISTs tend to push surrounding structures as opposed to invading them, if a GIST is adherent to a contiguous organ, it is necessary to remove the tumor en bloc with a portion of that organ.

The site and size of a primary GIST influence the surgical approach. For small- to medium-sized tumors, laparoscopic resection can be used. Some of these tumors will be cured by surgery alone as they generally tend to have low mitotic rates. Gastric GISTs are often easily identified at surgery because they tend to be exophytic. Tumors that grow more inward toward the gastric lumen may require intraoperative endoscopy to localize the exact site for partial gastrectomy. Intraoperative ultrasound may also be useful and is facilitated by instilling water into the stomach. Tumors arising from the posterior wall of the stomach are slightly more challenging to remove but still often can be removed laparoscopically after adequate stomach mobilization. It is often helpful during laparoscopy to retract the left lateral segment of the liver to the right to fully expose the stomach. Most gastric tumors can be removed using surgical staplers. Generally, a 1-cm margin of normal tissue is adequate. As Dr Raut mentions, it may not be possible or necessary to have a preoperative tissue diagnosis. Therefore, patients should be informed that their tumor may not prove to be a GIST. Other entities that can masquerade as GISTs include leiomyoma, Schwannoma, and even ectopic pancreas.

Occasionally, gastric GISTs arise near the gastroesophageal junction. In general, we prefer to remove these GISTs using laparotomy, especially if they arise from the posterior stomach. It may be necessary to open the stomach to facilitate adequate removal and proper reconstruction. If, instead, surgical staplers are used, it is advisable to use a bougie to avoid narrowing the entrance to the stomach.

Massive gastric tumors may be inseparable from the splenic hilum, distal pancreas, splenic flexure of the colon, or the fourth portion of the duodenum. In patients with large GISTs, neoadjuvant imatinib mesylate is highly recommended as it may reduce the extent of the operation required to remove the tumor. Generally, we perform a computed tomography (CT) 2–4 weeks after starting imatinib to check for tumor response, which can be detected by a decrease in tumor perfusion and density. Size is not a reliable indicator of response initially, because a responsive tumor may not decrease in size and occasionally may even swell temporarily. Therefore, it is important that the surgeon personally review the radiologic films. In the absence of tumor progression, imatinib is then continued and scans are repeated 3 and 6 months later. Generally, resection is attempted between 6 and 9 months following the start of a tyrosine kinase inhibitor. Rarely, a total gastrectomy is required to remove adequately a proximal gastric GIST, especially if it is large. This possibility should be discussed with the patient preoperatively.

The small intestine is the next most common site of origin. The same basic surgical principles apply. GISTs of the duodenum are particularly complex to treat. A GIST in the second portion of the duodenum may require a pancreaticoduodenectomy, unless it is on the lateral wall and small in size. In that case, a lateral duodenal resection can be performed. Reconstruction can be performed with a Roux-en-Y jejunal limb. Sometimes, though, the defect can be closed primarily. GISTs in the fourth portion of the duodenum can be removed and reconstructed with a direct anastomosis between the duodenum and jejunum or closure of the distal duodenum with a Roux-en-Y jejunal limb that is sewn to the second portion of the duodenum. Neoadjuvant imatinib therapy is often useful in duodenal GISTs.

Although colonic GISTs are rare, GISTs arise from the rectum 5% of the time. Neoadjuvant therapy may reduce the extent of the operation and in particular preserve the anal sphincter and avoid an abdominoperineal resection. For distal tumors, local resection can be performed via the transanal route. The value of postoperative radiation following the local excision of a rectal GIST is uncertain.

Unlike many cytotoxic chemotherapeutic agents, imatinib and sunitinib (as well as sorafenib, dasatinib, and nilotinib) can just be stopped a day or two prior to surgery. For patients requiring postoperative therapy, the agent can be restarted when the patient is tolerating a regular diet well, usually within 2 weeks of surgery.

As covered by Dr Raut, certain patients are considered for adjuvant therapy with imatinib following the resection of a primary, localized GIST. The results of a phase 3 trial demonstrated prolonged recurrence-free survival in patients assigned to 1 year of imatinib therapy compared with those assigned to placebo.3 Overall survival is not different at this time. This trial included “all comers” with a tumor at least 3 cm in size. Subsequent analyses have shown that patients at low risk of recurrence (see Table 24-1) probably do not benefit from adjuvant imatinib because the chance of tumor recurrence is so low.

Recently, we have developed a nomogram based on tumor size, location, and mitotic rate to provide a numerical estimation of recurrence-free survival for any particular patient (http://www.mskcc.org/mskcc/html/98103.cfm).4 The nomogram results can be used to guide the discussion of adjuvant therapy with a particular patient. As we accumulate more data on the impact of specific mutations in GIST, the nomogram will be further refined. The central question for patients who are at moderate to high risk of tumor recurrence and are receiving adjuvant imatinib is when the drug should be discontinued. It appears that 1 year of adjuvant imatinib may not be enough. As pointed out by Dr Raut, several ongoing trials are attempting to identify the optimal duration of adjuvant imatinib therapy.

The standard of care for metastatic GIST is treatment with tyrosine kinase inhibitors. However, in selected patients with resectable metastases, I and others have recommended surgical resection when all residual disease can be removed. Dr Raut references several retrospective series that have shown the safety of this approach. The results of course are confounded by selection bias. In addition, there is lead-time bias, because many of the patients underwent surgery early on after starting medical therapy. The true efficacy of surgery therefore remains unproven. The hypothesis is that the time to resistance to tyrosine kinase inhibition is proportional to the amount of residual tumor following the response to a tyrosine kinase inhibitor. There are two open trials in which patients are being randomized to a tyrosine kinase inhibitor with or without surgery. For obvious reasons, accrual may be problematic. As radiologic surveillance of patients who have undergone surgical removal of a primary GIST increases, it will become more commonplace to detect minimal amounts of metastatic disease that are amenable to surgical removal. In the absence of randomized data, it seems reasonable to perform surgery for metastatic GIST in well-informed patients when the disease has responded to tyrosine kinase inhibition and all the disease can be removed.