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Gastrointestinal Stromal Tumors Treatment & Management

  • Author: Nancy S Behazin, MD; Chief Editor: BS Anand, MD  more...
 
Updated: Mar 30, 2015
 

Medical Care

Imatinib is a selective small molecule inhibitor of a family of structurally similar tyrosine kinase signaling enzymes, including KIT, PDGFRA, and chronic myelogenous leukemia specific BCR-ABL protein. In laboratory studies, imatinib was shown to inhibit proliferation of BCR-ABL leukemic cells and GIST cells with KIT mutations.

Imatinib mesylate is indicated in patients with advanced GISTs. It is indicated as adjuvant therapy post complete surgical resection in patients with tumors that are stratified to be high risk (see Prognosis) and as neoadjuvant therapy, with the goal of tumor shrinkage prior to surgical resection.

Demetri et al in 2002 randomly assigned patients with metastatic or unresectable GIST to either 400 mg or 600 mg of imatinib. Imatinib induced an objective response in more than half of the patients. The early favorable results of this study led the FDA to approve imatinib for the treatment of KIT-positive unresectable or metastatic GIST in February 2002.[27]

DeMatteo et al in 2009, in a randomized, double-blind, placebo-controlled study showed adjuvant imatinib therapy to be safe and to improve recurrence-free survival compared with placebo after resection of a gastrointestinal tumor.[28]

Joensuu et al in 2012, in a randomized, placebo-controlled trial showed that patients assigned to 36 months of imatinib had longer recurrence-free survival compared with those assigned to 12 months of treatment (hazard ratio, 0.46; 95% confidence interval, 0.32-0.65; P < .001; 5-year recurrence-free survival, 65.6% vs 47.9%, respectively).[29] In some patients, imatinib fails immediately after initiation (primary resistance). Some patients initially show response to imatinib but later develop progressive disease (secondary resistance).[30]

Imatinib resistance may be managed by increasing the dose to 800 mg per day or switching directly to sunitinib.[30]

Sunitinib is another tyrosine kinase receptor inhibitor that is less specific than imatinib. Sunitinib inhibits KIT and PDGFR as well as vascular endothelial growth factor receptors (VEGFR1-3), Fms-related tyrosine kinase 3, colony-stimulating factor (CSF), and RET. Thus, sunitinib has both antiangiogenic and anti-tumor potential.[30]

Demetri et al in 2006 conducted a phase III double-blind study evaluating sunitinib versus placebo in patients with advanced GIST who were intolerant or refractory to imatinib. The time to disease progression was four times longer in those receiving sunitinib (27.3 vs 6.4 weeks for placebo; P < .0001). Progression-free survival and overall survival were better for patients treated with sunitinib.[31]

In January 2006, the FDA approved sunitinib as a second-line agent for patients with advanced GIST.

George et al in 2009 evaluated the safety and efficacy of sunitinib in patients with advanced GIST after imatinib failure. Results suggested that continuous daily dosing of sunitinib was an effective alternative with acceptable safety for patients with imatinib resistant GIST.[32]

Regorafenib (Stivarga) received FDA approval for locally advanced, unresectable GISTs that no longer respond to imatinib or sunitinib. The pivotal phase III GRID trial of 199 patients with metastatic or unresectable GIST showed that regorafenib plus best supportive care (BSC) significantly improved progression-free survival (PFS) compared to placebo plus BSC. Patients were treated with BSC and randomized in a 2:1 ratio to either regorafenib (160 mg daily for 3 weeks followed by a 1-week break) or placebo. Median PFS was 4.8 months for regorafenib and 0.9 months for placebo.[33, 34]

Investigational agents for patients with progressive disease despite imatinib and sunitinib use include the second-generation tyrosine kinase inhibitors: sorafenib, dasatinib, and nilotinib.

Consultations

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

Next

Surgical Care

Surgery is the definitive therapy for patients with GISTs. Radical and complete surgical extirpation offers the only chance for cure. Surgery is also indicated in symptomatic patients with locally advanced or metastatic disease. Debulking large lesions is helpful when adjuvant therapy with imatinib mesylate is contemplated.

In 2003, Wu et al published their experience with 57 patients who underwent surgical treatment of GISTs from 1995-2002.[35] Twenty-eight patients (49%) underwent surgery with curative intent. The remainder were referred to the authors with metastatic disease after undergoing operative treatment at other institutions. In the curative-intent group, resections with completely negative margins were accomplished in 22 patients (79%). In 3 of the patients with complete resections, metastatic disease was totally resected along with the primary tumor. An additional 2 patients had subsequent complete resection after favorable clinical responses to imatinib mesylate therapy. CD117 staining was positive in 96% of the resected specimens. In total, 34 patients were diagnosed with metastatic disease during the initial evaluation and treatment or at some point during follow-up. The most common sites of metastatic disease were the liver (71%) and peritoneum (53%).

The authors monitored the entire cohort for a median duration of 18 months. Twenty-three patients (40%) remained alive and free of disease. An additional 22 patients (39%) are alive with disease. Of the remainder, 7 are known to have died and 5 have been lost to follow-up. Treatment with imatinib effected disease stabilization or regression in 22 (85%) of the 26 treated, with a median duration of response of 19 months.

The authors concluded that complete resection with negative margins is still the only potentially curative treatment of GISTs. Furthermore, imatinib therapy for metastatic disease is associated with good clinical response rates, but the true therapeutic efficacy of this drug will not be known until prospective trials are completed.

In 2003, Besana-Ciani et al reported on 19 patients with GISTs who underwent surgical resection.[36] They were able to achieve complete resection in 78.9% of patients in this series. The mean tumor size was 8.4 cm. These patients received long-term follow-up. Using the Fletcher et al histologic classification, tumors were divided into 2 groups.[24] Tumors classified as very low, low, and intermediate risk comprised one group. The second consisted of tumors classified as high risk. The 5-year survival rates were 63% in the former group and 34% in the latter group. As might be expected, complete resection was also a significant predictor of superior survival compared with incomplete resection. These authors also concluded that radical complete resection offers the only chance for long-term survival in patients with GISTs.

Laparoscopic resection has improved and is a more frequently considered option for patients with a GIST. Chen et al studied 58 patients diagnosed with GISTs from 2005-2010. Of these, 16 underwent laparoscopic surgery and 42 underwent open surgery. It was concluded that laparoscopic surgery was technically possible for GISTs no larger than 5 cm located at the stomach and small bowel. The patients benefited from fewer days until resuming a normal diet, shorter postoperative hospital stays, and less analgesia use. The patients experienced the same short-term oncology result as the patients who underwent open surgery.[37]

In 2012, El-Gendi et al reported on 12 patients who underwent limited duodenal resection for primary nonmetastatic duodenal GIST since 2002. The authors concluded that limited resection is a reliable option for disease-free survival depending on tumor size, adjacent organ involvement, and location.[38]

Preoperative imatinib should be considered if surgical morbidity would be improved by cytoreducing the size of the tumor.

Postoperative imatinib has been shown to increase recurrence-free survival after complete resection of localized GIST. In 2012, Joensuu et al showed that compared with 12 months of adjuvant imatinib, 36 months of imatinib improved recurrence free survival and overall survival of GIST patients with a high risk of GIST recurrence.[29]

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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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Contributor Information and Disclosures
Author

Nancy S Behazin, MD Fellow, Department of Gastroenterology, Scott and White Hospital, Texas A&M Health Science Center College of Medicine

Nancy S Behazin, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Medical Association, American Society for Gastrointestinal Endoscopy, Texas Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Noel Williams, MD, FRCPC FACP, MACG, Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor, Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada

Noel Williams, MD, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

Robert A Decker, MD Clinical Assistant Professor, Department of Medicine, University of Hawaii at Manoa: Chief, Gastroenterology Service, Kaiser Permanente Medical Center of Honolulu

Disclosure: Nothing to disclose.

Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Michael AJ Sawyer, MD Consulting Staff, Department of Surgery, Southwestern Medical Center; Consulting Staff, Department of Surgery, Comanche County Memorial Hospital; Consulting Staff, Great Plains Surgical Clinic, Inc

Michael AJ Sawyer, MD is a member of the following medical societies: American College of Surgeons, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, and Society of Laparoendoscopic Surgeons

Disclosure: Nothing to disclose.

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