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Intestinal Stromal Tumors Treatment & Management

  • Author: Michael A Choti, MD, MBA, FACS; Chief Editor: Jules E Harris, MD, FACP, FRCPC  more...
 
Updated: Apr 28, 2015
 

Medical Care

In general, attempts to treat GISTs with cytotoxic chemotherapy or radiation therapy have been unsuccessful. Effects of radiation therapy on survival are unknown. GISTs are not ideal for this modality because of intra-abdominal motility, and for large tumors, the required field of radiation exposure may cause too much morbidity. Most often, radiation therapy is used in the palliative setting for symptomatic, unresectable disease. Standard cytotoxic chemotherapy has not been helpful in GIST management. One report noted only a 7% response rate (3 of 43 people with GISTs) to doxorubicin and dacarbazine in gastric sarcomas, compared with 22% for leiomyosarcomas. Other chemotherapy combinations have been equally unsuccessful. There is universal agreement that chemotherapy should not be used in patients with GISTs.

Imatinib mesylate (Gleevec), a tyrosine kinase inhibitor, is the first drug that effectively showed response rates against GIST progression.[25, 26, 27] The US Food and Drug Administration (FDA) has approved imatinib for adjuvant therapy of completely resected GISTs in adult patients. The efficacy of imatinib has also altered the paradigm in the treatment of patients with inoperable disease related to the difficulty in achieving negative margins or the risk of severe organ dysfunction. In these patients, imatinib therapy may be given in the neoadjuvant setting to shrink the tumor, with later surgical intervention for a complete resection.[28, 29]

Currently, for most cases of metastatic disease, imatinib therapy is considered the first-line treatment. Due to the success of imatinib therapy, 70% of patients with metastatic disease live more than 2 years after starting therapy; median overall survival is over 4 years.[30] In comparison, only 20% of patients with metastatic disease treated with doxorubicin had a 2-year survival. Present recommendations are for life-long treatment with imatinib for metastatic disease.

The use of imatinib can be guided by genotyping of KIT and PDGFRA mutations[31] :

  • KIT exon 11 mutants respond well to imatinib.
  • KIT exon 9 Ala502_Tyr503dup mutants, which occur predominantly in intestinal GISTs, are less sensitive to imatinib. 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. [32]
  • GISTs with an Asp842Val substitution in exon 18, the most common PDGFRA mutation, are resistant to imatinib.
  • GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib.

An international phase III trial in 906 patients with advanced GI stromal tumors found that long-term benefit from imatinib mesylate treatment can be predicted early on through the use of Response Evaluation Criteria in Solid Tumors (RECIST[33] ) classification. Classification of patients at 2 and 4 months as showing response, no change, or progressive disease proved to be highly predictive of further progression or survival. When patients were classified after 6 months of imatinib, however, survival prognosis was the same among responders and those showing no change. These investigators suggest that imatinib be continued as long as patients show no progression according to RECIST.[34]

Sunitinib malate, a multikinase inhibitor, is considered the standard second-line therapy for GISTs.[35] The principal support for sunitinib in this role is a study by Demetri et al that reported significant disease control and superior survival with sunitinib compared with placebo in 312 patients with advanced GIST after failure and discontinuation of imatinab.[36] The FDA has approved sunitinib for use in patients with GISTs that are not responding to imatinib or for patients who cannot tolerate imatinib.

Regorafenib (Stivarga) was approved in February 2013 for locally advanced, unresectable GISTs that no longer respond to imatinib or sunitinib. The pivotal phase III GRID trial showed that regorafenib plus best supportive care (BSC) significantly improved progression-free survival (PFS) compared to placebo plus BSC. Median PFS was 4.8 months for regorafenib and 0.9 months for placebo.[37]

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Surgical Care

Surgical resection remains the cornerstone of treatment for localized GISTs. A complete resection offers the only chance for cure. Patients with complete tumor resection have a clear survival benefit over those with less radical or no surgery. Complete resection is associated with approximately 50-65% 5-year survival rate, but more than 50% of patients who undergo primary resection develop tumor recurrence (see Table 1 in Mortality/Morbidity).

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. 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. Laparoscopic resection of GISTs of the stomach has demonstrated the feasibility and safety of this technique.

Approach all GISTs with an intention of a complete en bloc resection, including resection of any involved organs or structures such as the colon, spleen, kidney, and pancreas. As GISTs rarely metastasize to lymph nodes, routine lymphadenectomy is not indicated and does not show any survival benefit. Direct all efforts at avoiding tumor rupture during the operation. A tumor rupture is associated with a worse prognosis due to peritoneal seeding. Similarly, preoperative percutaneous biopsy of the tumor is not indicated in most cases, because there is a potential for needle track seeding. Preoperative percutaneous biopsy is pursued if the newly available information changes management, as it would in the case of a lymphoma.

The role for surgery in treating GIST metastasis is minimal. Metastasectomy may provide a survival benefit in select patients. These may include patients with well-differentiated GISTs, longstanding disease-free survival, and isolated liver metastases. In patients with good response to imatinib treatment, in whom gross disease can be removed, surgery may be considered on an individual case-by-case basis.

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Consultations

No specific consultations are required.

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Diet

Decisions regarding postoperative diet are based on the type of surgery and are individualized. No specific diet restrictions are recommended for people with GISTs.

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Activity

No specific activity restrictions exist.

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Contributor Information and Disclosures
Author

Michael A Choti, MD, MBA, FACS Hall and Mary Lucile Shannon Professor and Chair, Department of Surgery, University of Texas Southwestern Medical Center

Michael A Choti, MD, MBA, FACS is a member of the following medical societies: American Association for the Study of Liver Diseases, American Surgical Association, International Hepato-Pancreato-Biliary Association, Americas Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology, American College of Surgeons, Association for Academic Surgery, Society for Surgery of the Alimentary Tract, Society of Surgical Oncology, Society of University Surgeons

Disclosure: Nothing to disclose.

Coauthor(s)

Fabian M Johnston, MD, MHS, FACS Assistant Professor, Department of Surgery, Johns Hopkins University School of Medicine

Fabian M Johnston, MD, MHS, FACS is a member of the following medical societies: American Medical Association, National Medical Association, Society of Black Academic Surgeons, Society of Surgical Oncology

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.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Jules E Harris, MD, FACP, FRCPC Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Jules E Harris, MD, FACP, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Society of Hematology, Central Society for Clinical and Translational Research, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Additional Contributors

Robert C Shepard, MD, FACP Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International

Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American Association for Physician Leadership, European Society for Medical Oncology, Association of Clinical Research Professionals, American Federation for Clinical Research, Eastern Cooperative Oncology Group, Society for Immunotherapy of Cancer, American Medical Informatics Association, American College of Physicians, American Federation for Medical Research, American Medical Association, American Society of Hematology, Massachusetts Medical Society

Disclosure: Nothing to disclose.

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Gastric stromal tumor: Gross specimen following partial gastrectomy. Note the submucosal tumor mass with the classic features of central umbilication and ulceration. Image courtesy of Michael Choti, MD.
CT scan of the abdomen with oral contrast in a 60-year-old woman with gastric stromal tumor. A huge mass with central necrosis is observed originating from the gastric wall and narrowing its lumen. An ulcer crater can be identified within the mass (arrow). Image courtesy of Michael Choti, MD.
Gastric stromal tumor. Photomicrograph of gastrointestinal stromal tumor (GIST) stained with hematoxylin and eosin (H&E) and magnified 40 times. Note the solid sheet of spindle cells. Image courtesy of Michael Choti, MD.
Photomicrograph of a gastric stromal tumor stained with hematoxylin and eosin (H&E) and magnified 400 times. This stromal tumor demonstrates spindle cells with epithelioid features. Image courtesy of Michael Choti, MD.
Gastric stromal tumor: Photomicrograph of gastrointestinal stromal tumor (GIST) with immunohistochemical staining for CD117. Note the strong positive staining of tumor cells with negative staining of the adjacent vessel. Positive stain for CD117 is diagnostic of GIST. Image courtesy of Michael Choti, MD.
Liver resection specimen demonstrating 2 hepatic metastases from a gastrointestinal stromal tumor. Image courtesy of Michael Choti, MD.
Table 1. Survival in Patients Undergoing Resection of GISTs [12, 13, 14, 15, 16, 17]
Reference Period Patients, No. Complete Resections, No. 5-y Survival Rate After Complete Resection, %
Caterino et al 1999-2009 47 46 65
DeMatteo et al 1982-1998 200 80 54
Ng et al 1957-1997 191 99 48
McGrath et al 1951-1984 51 30 63
Shiu et al 1949-1973 38 20 65
Akwari et al 1950-1974 108 52 50
Table 2. Risk Classification for Primary GIST by Mitotic Index, Size, and Tumor Site. Adapted from AJCC.
Tumor Parameters Risk of Progressive Disease*
Mitotic



Index



Size Stomach Duodenum Jejunum



or ileum



Rectum
 



≤5 per 50 HPF



≤2cm None None None None
>2 to ≤5 cm Very low (1.9%) Low (8.3%) Low (4.3%) Low (8.5%)
>5 to ≤10 cm Low (3.6%) Insufficient data Moderate (24%) Insufficient data
>10 cm Moderate (10%) High (34%) High (52%) High (57%)
 



>5 per 50 HPF



≤2 cm None* Insufficient data High † High (54%)
>2 to ≤5 cm Moderate (16%) High (50%) High (73%) High (52%)
>5 to ≤10 cm High (55%) Insufficient data High (85%) Insufficient data
>10 cm High (86%) High (86%) High (90%) High (71%)
*Defined as metastasis or tumor-related death.



† Denotes small number of cases.



Data based on long-term follow up of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs.
Table 3. Proposed Staging System for Malignant Gastrointestinal Stromal Tumors [24]
Group T N M Mitosis
Stage I T1 or T2 N0 M0 Low
Stage II T3 N0 M0 Low
Stage IIIA T1 N0 M0 High
  T4 N0 M0 Low
Stage IIIB T2 N0 M0 High
  T3 N0 M0 High
  T4 N0 M0 High
Stage IV Any T N1 M0 Any Rate
  Any T Any N M1 Any Rate
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