Gastrointestinal Stromal Tumors (GISTs) Treatment & Management

When feasible, surgical resection is the treatment of choice for gastrointestinal stromal tumors (GISTs) and offers the only chance for cure. Medical therapy is indicated in the following four scenarios ^{[5, 39, 52, 53]} :

• Preoperatively, to enable resectability or decrease morbidity by shrinking the tumor
• After surgery, to decrease recurrence
• In metastatic disease, as definitive treatment
• In recurrent, unresectable disease, as definitive treatment

Medical therapy consists of tyrosine kinase inhibitors (TKI), with the most commonly recommended first-line agent being imatinib mesylate (Gleevec). 

Imatinib is the standard choice for adjuvant therapy of GISTs, as well as for treatment of locally advanced inoperable and metastatic GISTs, but GISTs vary in their response to imatinib. ^{[25, 39]}  The use of imatinib can be guided by genotyping of KIT and PDGFRA mutations. ^{[25, 54]} 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. ^{[55, 56]}

Most GISTs with PDGFRA gene mutations respond to imatinib, with the notable exception of those with D842V. ^[39] 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; however, neoadjuvant avapritinib may be considered in such patients if R0 surgery is not feasible or is likely to result in major sequelae. ^[25]

GISTs with mutations in the succinate dehydrogenase (SDH) gene that result in deficiency of SDH are also generally resistant to TKI therapy, although theoretically these tumors may have greater sensitivity to TKIs with a prominent antiangiogenic mechanism of action (eg, sunitinib, regorafenib). ^[57] Surgical resection is the mainstay of treatment for localized tumors in these patients, but recurrence is common. Clinical trials of systemic agents for treatment of advanced SDH-deficient GIST are currently in progress. ^[58] Referral of these patients to specialized centers is recommended. ^[57]

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 reduced their dose due to severe toxicities, responses have been observed with a dose as low as 100 mg.

In patients who received imatinib preoperatively and whose GIST was completely resected, the National Comprehensive Cancer Network (NCCN) recommends considering continuation of imatinib postoperatively. Although treatment duration in this setting has not been studied in randomized trials, data support continuation for 3 years postoperatively. ^[39]

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. ^[59]

In 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). ^[60]

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. ^[25]

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. ^[25]

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 TKI that has been shown to provide significant clinical benefit in imatinib-resistant advanced GIST. GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib.

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. ^[61]

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 TKI 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. ^[62]  Additional chemotherapeutic agents include sorafenib, dasatinib and pazopanib.

In January 2020, the FDA approved avapritinib (Ayvakit), another TKI that inhibits PDGFRA. Avapritinib targets PDGFRA and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17, and 17 mutants. It is indicated for adults with unresectable or metastatic GIST harboring PDGFRA exon 18 mutations, including PDGFRA D842V mutations. 

Avapritinib approval for PDGFRA-mutant GIST was based on the NAVIGATOR and VOYAGER clinical trials. Results demonstrated durable responses in patients with PDGFRA exon 18 mutations across multiple lines of treatment. In these patients (n=43), the objective response rate (ORR) was 84% (7% complete response [CR], 77% partial response [PR]). In patients with PDGFRA D842V mutations (n=38), the ORR was 89% (95% CI: 75%, 97%; 8% CR, 82% PR). While the median duration of response was not reached, 61% of the responding patients with exon 18 mutations had a response lasting 6 months or longer (31% of patients with an ongoing response were followed for less than 6 months). ^{[63, 64]}

Ripretinib (Qinlock) was approved for advanced GIST in previously treated patients in May 2020.

Approval was based on an international multicenter, double-blind, and placebo-controlled trial, INVICTUS, that enrolled previously treated patients (n=129) with unresectable, locally advanced or metastatic GIST. The median PFS and ORR was 6.3 months and 9% in the ripretinib arm compare to 1 month and 0% in the placebo arm. ^[65]

Adjuvant tyrosine kinase inhibitor therapy 

Use of adjuvant TKI therapy after surgical resection is guided by the estimated maligant potential. The NCCN has proposed guidelines for estimating the malignant potential of GISTs, based on tumor size and mitotic rate and stratified by gastric or non-gastric origin. ^[39]  These are listed in Tables 4 and 5, below. 

Table 4. Malignant Potential of Gastric GISTs (NCCN) (Open Table in a new window)

 

Table 5. Malignant Potential of Non-Gastric GISTs (NCCN) (Open Table in a new window)

 

Surgery is the definitive therapy for localized GISTs. ^[25] 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 of GIST. ^{[66, 67, 68, 69, 70]}

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. ^[71]  Zhao et al reported tht endoscopic full-thickness resection (EFR) is feasible for gastric GISTs of up to 5.0 cm in size; although the R0 resection rate was significantly lower with EFR (95.3%) than with laparoscopic or surgical resection (100%), EFR involved significantly fewer postoperative complications, shorter length of hospital stay, and lower cost. ^[72]

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, ^[73] there may be a role for cytoreductive surgery (R0 or R1 resection) in the setting of recurrent metastatic disease confined to the abdomen. ^[74] 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. ^[75]

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). ^[39]

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. ^[76]

Numerous published reports of laparoscopic resection of gastric GISTs have demonstrated the feasibility and safety of this technique. ^{[77, 78, 79, 80, 81, 35]}  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. ^[36]

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.

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

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

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.

Follow-up care after curative operations is important because certain patients with recurrent disease may benefit from second surgical intervention and from systemic therapy with tyrosine kinase inhibitors for unresectable and/or metastatic disease. Follow-up includes physical examination and computed tomography (CT) scanning, and possibly periodical gastroscopies, as well.

For followup of gastric GISTs < 2 cm that have been completely resected, the National Comprehensive Cancer Network (NCCN) recommendations vary according to the presence or absence of high-risk features (eg, irregular border, cystic spaces, ulceration, echogenic foci, heterogeneity). For GISTs with high-risk features, the NCCN recommends considering abdominal/pelvic CT with contrast every 3-6 months for 5 years, then annually. For those without high-risk features, endoscopic surveillance at 6-12 month intervals may be considered. ^[39]

For followup of patients with metastic or persistent gross residual disease, the NCCN recommends followup with history and physical examination and abdominal/pelvic CT every 3-6 months. For patients with completely resected GISTs, the NCCN recommends history, physical examination and abdominal/pelvic CT every 3-6 months for 5 years, then annually. ^[39]