Gastrointestinal Stromal Tumors (GISTs) Treatment & Management

Updated: Sep 28, 2016
  • Author: Michael A Choti, MD, MBA, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Treatment

Medical Care

Although surgical resection is the treatment of choice for gastrointestinal stromal tumors (GISTs) and offers the only chance for cure, the tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec) plays a major role. [4, 36, 44, 45] The uses of imatinib include the following [36] :

  • Treatment of GISTS that are unresectable, metastatic, or both
  • Preoperative treatment of GISTs that are resectable with negative margins but with risk of significant morbidity
  • Adjuvant treatment following complete gross resection of GIST, to reduce recurrence

The use of imatinib can be guided by genotyping of KIT and PDGFRA mutations. [29, 46] Imatinib shows the highest activity in GISTs that contain the mutation in exon 11 of KIT; approximately 90% of those patients respond. KIT exon 9 Ala502_Tyr503dup mutations, which occur predominantly in intestinal GISTs, are less sensitive to imatinib; approximately 50% respond. To improve response in these patients, a recommended regimen is to initiate imatinib at the standard dose of 400 mg daily and then escalate to 800 mg daily, if tolerated, over approximately 1 month. [47]

GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib.

Most GISTs with PDGFRA gene mutations respond, with the notable exception of those with D842V. [36] There is consensus that patients whose GISTs have the PDGFRA D842V mutation should not be treated with any adjuvant therapy, given the lack of sensitivity of this genotype [29]

Imatinib comes in 100-mg tablets and can thus be given in graduated doses (100, 200, 300, 400, 500, 600, 700, 800 mg) while monitoring treatment responses. The adverse reactions of imatinib are manageable and include edema, rash, diarrhea, nausea, abdominal pain, and fatigue. Treatment interruption or dose reduction may be necessary in patients who develop severe hepatotoxicity or other severe adverse reactions.

In patients who have had their dose reduced due to severe toxicities, responses have been observed with a dose as low as 100 mg. Importantly, clinical trials have determined the efficacy of commonly prescribed doses (400, 600, and 800 mg). In general, doses below 300 mg should be avoided. The maximum tolerated dose of imatinib is 800 mg/d.

The standard dose of imatinib is 400 mg by mouth daily. The prescribed dose should be taken with a low-fat meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.

In patients who received imatinib preoperatively and whose GIST was completely resected, the National Comprehensive Cancer Network recommends considering continuation of imatinib postoperatively. Although the duration of imatinib use in this setting has not been studied in randomized trials, data support continuation for 2 years postoperatively. [36]

The use of imatinib as adjuvant therapy to prevent recurrence of primary GIST was approved by the US Food and Drug Administration (FDA) in 2008. [4, 48] In January 2012, the FDA extended the approved duration of use from 1 year to 3 years following surgical removal of CD117-positive GISTs. The approval was based on a randomized study in 400 patients with KIT (CD117)–positive GISTs, which found that at the median 5-year follow-up, overall survival was greater in patients treated for 3 years than in those treated for 1 year (92% vs 82%; hazard ratio [HR], 0.45; P = 0.019); 5-year relapse-free survival was also significantly superior (65.6% vs 47.9%; HR, 0.46; P< 0.0001). [49]

The European Society for Medical Oncology (ESMO) advises that evaluation of response to treatment is complex and that early progression, in particular, should be confirmed by an experienced team. In most cases, anti-tumor activity is indicated by tumor shrinkage but in some, tumor response is indicated only by a decrease in tumor density, or decreased density may precede delayed tumor shrinkage. [29]

Even an increase in the tumor size may indicate tumor response if the tumor density on CT scan is decreased. Even the appearance of seemingly new lesions may be due to pre-existing lesions becoming more evident when they become less dense. [29]

Therefore, ESMO recommends using both tumor size and tumor density on CT scan, or consistent changes in MRI or contrast-enhanced ultrasound, as criteria for tumor response. 2-[F-18]-fluoro-2-deoxy-D-glucose (18-FDG PET) scanning has proved highly sensitive in early assessment of tumor response and may be useful in cases where there is doubt, or when early prediction of the response is particularly useful (eg, preoperative cytoreductive treatments). A small proportion of GISTs have no FDG uptake, however.

The absence of tumor progression after 6 months of treatment also amounts to a tumor response, according to ESMO. On the other hand, tumor progression may occur without changes in the tumor size; such cases may be indicated by increased density within tumor lesions. A typical progression pattern is the “nodule within the mass,” in which a portion of a responding lesion becomes hyperdense.

In the setting of metastatic/advanced GIST, the NCCN recommends continuous use of imatinib until clear evidence of progression occurs. For progressive disease, the imatinib dosage may be increased to 800 mg daily for patients with acceptable performance status (Eastern Cooper ative Oncology Group [ECOG] score 0-2), or therapy may be switched to sunitinib (Sutent), a newer tyrosine kinase inhibitor that has been shown to provide significant clinical benefit in imatinib-resistant advanced GIST.

The FDA approved sunitinib in 2006 for the treatment of patients with GISTs whose disease has progressed or who are unable to tolerate treatment with imatinib. An interim analysis showed that sunitinib treatment delayed the median time to tumor progression of GISTs to 27 weeks, as compared with 6 weeks for patients who did not receive the drug.

The TKI regorafenib (Stivarga) receive FDA approval in February 2013 for locally advanced, unresectable GISTs that no longer respond to imatinib or sunitinib. The pivotal phase III trial showed that regorafenib plus best supportive care (BSC) significantly improved progression-free survival (PFS) compared with placebo plus BSC. Median PFS was 4.8 months for regorafenib and 0.9 months for placebo. [50]

In a meta-analysis of three randomized, controlled studies in GIST patients with imatinib resistance or intolerance who received treatment with sunitinib, nilotinib, or regorafenib (n = 541) or placebo/supportive care (n = 267), progression-free survival, but not overall survival, significantly improved in the tyrosine kinase inhibitor treatment group. In patients with resistance or intolerance to both imatinib and sunitinib, treatment with nilotinib or regorafenib improved progression-free, but not overall survival. [51]

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Surgical Care

Surgery is the definitive therapy for localized GISTs. [29] Despite the proven success of imatinib and other newer tyrosine kinase inhibitors, surgical resection remains the treatment of choice and offers the only chance for cure from GIST. [52, 53, 54, 55, 56, 57]

The main operative principle is resection of the tumor with negative microscopic margins. Wide resection of the tumor (eg, 2-cm margin) has not been shown to improve outcomes and expert consensus is that dogmatic adherence to a particular width of margin is not necessary or recommended.

For small GISTs, local resection may be adequate, if it is technically possible and does not compromise a complete resection. Small intestinal tumors may require segmental resection, and a wedge resection may be used for small gastric GISTs in some cases. [58] Avoid enucleation of small tumors, since predicting the preoperative malignant potential of GISTs is difficult even if the tumor appears benign. Since limited resection is adequate for small malignant GISTs, minimally invasive surgery techniques can be adopted in select cases.

For locally invasive tumors, en bloc resection of adjacent involved organs, such as colon, spleen, or liver, may be indicated. Routine lymphadenectomy is not indicated, as lymph node involvement is very rare.

Recurrence and survival are not associated with the type of resection (wedge resection versus any type of gastrectomy) provided that a complete resection (R0) is performed.

Direct every effort at avoiding tumor rupture during the operation. Tumor rupture is associated with a worse prognosis because of peritoneal seeding.

In cases of disseminated disease, consider palliative resection, because long-term survival has been reported in certain cases. Also consider resection in patients with recurrent disease that manifests as a solitary lesion in the liver or peritoneal cavity. Published reports of liver resection for hepatic metastasis from gastric and other GISTs suggest a survival benefit in selected patients.

Given the ability of imatinib to render initially inoperable GIST tumors resectable, [59] there may be a role for cytoreductive surgery (R0 or R1 resection) in the setting of recurrent metastatic disease confined to the abdomen. [60] Patients should have been on at least 6 months of therapy with imatinib or another tyrosine kinase inhibitor and have had either stable or partially responsive disease during this period.

A significant minority of these patients require liver resections (40%) and the majority require multivisceral resection, including bowel resections, peritonectomy, and/or omentectomy (60%). Even after such aggressive resection, R1 resections (microscopically positive resections) are the rule, R0 resections are rare, and about 5% of patients still have bulky disease remaining.

Up to 70% of patients able to undergo an R0/R1 resection in the setting of stable or partially responsive disease enjoy a progression-free survival as long as 4 years after the initiation of imatinib therapy. [61]

Because adequate resection for small malignant GISTs can be achieved by wedge resection, minimally invasive surgery techniques can be considered in selected cases, such as those in favorable anatomic locations (eg, the greater curvature or anterior wall of the stomach). [36]

Laparoscopic surgery

Laparoscopic resection is increasingly used for treatment of GISTs. A study by Chen et al concluded that laparoscopic surgery was technically possible for GISTs no larger than 5 cm located at the stomach and small bowel. Benefits of laparoscopic resection included faster resumption of a normal diet, shorter postoperative hospital stays, and less analgesia use. Short-term oncology results were the same with laparoscopy as with open surgery. [62]

Numerous published reports of laparoscopic resection of gastric GISTs have demonstrated the feasibility and safety of this technique. [63, 64, 65, 66, 67, 68]  In a retrospective study of 666 patients who underwent primary resection for a gastric GIST smaller than 20 cm, Piessen et al reported that laparoscopic treatment of gastric GISTs was associated with significantly lower overall, surgical, and medical morbidity, and significantly better 5-year recurrence-free survival (RFS). In addition, subgroup analysis of patients with tumors larger than 5 cm found that laparoscopic and open approaches yielded comparable in-hospital morbidity and 5-year RFS. [69]

 

Postoperative care

Depending on the type of resection, a nasogastric tube is left in place postoperatively. Ensuring that the tube is continuously functional and remains unclogged is crucial. Criteria for removal of a nasogastric tube vary by clinician.

A urinary Foley catheter remains in place in the early postoperative period or during the preoperative resuscitative period in patients who have sustained major hemorrhage or other complications. The catheter aids monitoring of hydration status and serves as a guide for fluid resuscitation. Once the patient is stabilized and no additional major fluid shifts are anticipated, the catheter can be removed.

Pulmonary toilet

Instruct patients to cough and to take frequent deep breaths. The incentive spirometer is an important adjunct for this and should be used by the patient every 1-2 hours while awake. Early mobilization of the patient assists with maintaining good pulmonary toilet.

Monitoring

Vital signs are monitored per protocol. Intake and output records are kept. Pulse oximetry is used when appropriate to measure oxygen saturation.

Antibiotics

Unless bowel perforation or other septic complications have occurred, a single dose of intravenous antibiotic prophylaxis against wound infection is usually sufficient.

Patients with abdominal catastrophes such as bowel perforation or infarction require a full therapeutic course of intravenous antibiotics that cover the spectrum of gut flora.

Pain control, deep venous thrombosis prophylaxis, and aspiration precautions

An epidural catheter can be placed by anesthesia personnel for postoperative pain control. Alternately, a patient-controlled anesthesia schedule can be ordered.

Prophylaxis against deep venous thrombosis is crucial because it and pulmonary embolism are significant sources of postoperative morbidity and mortality. Available modalities include subcutaneous heparin, subcutaneous fractionated heparin preparations, and sequential compression stockings.

The head of the bed can be kept elevated 30-45°, or sometimes higher for elderly patients or during sleep, to help prevent aspiration.

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Complications

Complications can be divided into preoperative and postoperative categories. Preoperative tumor-related complications usually occur with tumors larger than 4 cm.

Major preoperative complications include the following:

  • Hemorrhage
  • Bowel obstruction
  • Volvulus
  • Intussusception
  • Bowel perforation with peritonitis

The range of postoperative complications is similar to that for major abdominal and GI surgery. The following is a representative but not exhaustive list:

  • Wound infection
  • Wound dehiscence with or without evisceration
  • Urinary tract infection
  • Atelectasis
  • Pneumonia
  • Anastomotic disruption
  • Anastomotic stricture
  • Marginal ulceration
  • Intra-abdominal abscess formation
  • Cholangitis
  • Delayed gastric emptying or gastroparesis
  • Internal or enterocutaneous fistula
  • Small bowel obstruction
  • Dumping syndrome
  • Alkaline reflux gastritis
  • Cardiac arrhythmias
  • Myocardial infarction
  • Deep venous thrombosis
  • Pulmonary embolism
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Consultations

The management of GISTs requires the participation of a multidisciplinary team. The team should include a surgeon, gastroenterologist, and medical oncologist.

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Diet

Postoperatively, patients receive nothing by mouth for varying durations, depending on the preference of the operating surgeon. Following nasogastric tube removal, patients can be started on a liquid diet and advanced to a full diet as tolerated. Postgastrectomy diet counseling by a registered dietitian is helpful in patients undergoing subtotal or total gastrectomies.

Depending on the patient's preoperative nutritional status, a period of specialized nutritional support might be indicated. This can range from enteral tube feedings to peripheral hyperalimentation to total parenteral nutrition. Multivitamin and iron supplementation may be indicated.

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