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Gastrointestinal Cancer
The Role of Imatinib Following Complete Resection of
Primary Gastrointestinal Stromal Tumors
Burton L Eisenberg, MD
Professor of Surgery, Section of Surgical Oncology, Dartmouth Medical School/Dartmouth-Hitchcock Medical Center
Abstract
Gastrointestinal stromal tumor (GIST) is a life-threatening disease, for which surgery is the standard of care. However, surgical resection of the
primary tumor is associated with a high rate of recurrence and a low five-year overall survival (OS) rate. The introduction of the KIT protein
kinase-targeted therapy imatinib mesylate has enhanced treatment options. It has demonstrated improvements in progression-free survival
and OS in patients with unresectable and/or metastatic malignant GISTs. Based on this efficacy, imatinib has been evaluated as an adjuvant
option in KIT-positive primary GIST patients who have undergone complete gross resection. Early data indicate that one-year adjuvant therapy
with imatinib 400mg/day can prolong recurrence-free survival (RFS) in these patients. Preliminary data also indicate potential benefits of a
higher imatinib dose (800mg/day) and a longer duration of adjuvant imatinib therapy. Currently, imatinib, at a recommended dose of
400mg/day, is approved by the US Food and Drug Administration (FDA) as an adjuvant therapy in adult patients who have undergone complete
gross resection of KIT-positive GIST.
Keywords
Primary gastrointestinal stromal tumor (GIST), surgery, recurrence-free survival, adjuvant therapy, imatinib mesylate
Disclosure: Burton L Eisenberg, MD, is a member of the advisory board of Novartis, and has received honoraria from Novartis.
Received: March 20, 2009 Accepted: April 17, 2009
Correspondence: Burton L Eisenberg, MD, Norris Cotton Cancer Center, 8th Floor, Rubin Building, One Medical Center Dr, Lebanon, NH 03756. E:
burton.l.eisenberg@dartmouth.edu
Gastrointestinal stromal tumor (GIST) is the most prevalent tumor growth. While surgery remains the standard of care for GIST,
mesenchymal tumor of the gastrointestinal tract, primarily arising in the imatinib therapy has altered the treatment paradigm. Imatinib has
stomach and small intestine.
1,2
It can be a life-threatening disease, with been shown to induce partial response or stable disease in 80% of
an expected incidence of approximately 5,000 new cases each year in patients with metastatic GIST.
24,25
In both unresectable and/or
the US.
3,4
Surgery is the standard of care for primary GISTs and the goal metastatic GIST patients, imatinib therapy has demonstrated durable
of resection is to completely remove the tumor with clear margins.
5,6
As response rates and favorable progression-free survival (PFS) and
GISTs are soft and fragile, surgical resection needs to be performed overall survival (OS).
24–27
The US Food and Drug Administration (FDA)
carefully to avoid tumor rupture or hemorrhage, with a resultant has approved imatinib for the treatment of patients with KIT-positive
increased risk for tumor dissemination.
5,7,8
Surgery may not always be unresectable and/or metastatic malignant GIST. The recommended
indicated, especially in instances of metastatic or locally advanced GIST. dose of imatinib is 400mg/day. The US-specific prescribing notes state
Prior to the approval of the targeted agent imatinib, there were no other that a dose increase to 800mg/daily (given as 400mg twice daily) may
effective therapies for metastatic GIST as both radiotherapy and be considered depending on the impact of the lower dose (400mg/day)
conventional chemotherapy were generally ineffective.
5,9–14
on disease progression.
Imatinib mesylate (Gleevec
®
, Novartis) is a potent inhibitor of several Around 46% of GIST patients are candidates for surgery, and the tumor
receptor protein tyrosine kinases including KIT, platelet-derived growth can be completely resected in most of these patients;
28–31
however,
factor, and BCR/ABL.
15–19
Its use in GIST is based on the fact that most 40–90% of these patients have a documented recurrence within two
GISTs express KIT, and up to 90% of patients have a c-kit or PDGFR- years of surgery with median disease-free survival (DFS) as low as
alpha gene mutation.
16,20,21
GISTs frequently result from gain-of-function three years.
28–31
Furthermore, the five-year OS rate after complete
mutations in the c-kit gene, which encodes the transmembrane surgical resection is only about 48–65%.
29,32–34
This has led to the search
tyrosine kinase KIT.
16,20–23
Once this mutated gene is expressed, KIT for an adjuvant therapy option to prevent or delay recurrence and,
signaling is constitutively activated, resulting in uncontrolled cell hopefully, to improve OS rates. Imatinib is currently being evaluated in
proliferation and resistance to apoptosis.
20–22
In GIST, imatinib primarily the adjuvant setting for primary GIST treatment, and the published data
acts by inhibiting this pathophysiological pathway, thereby inhibiting from the adjuvant trials will be discussed in this article. The rationale for
58 © TOUCH BRIEFINGS 2009
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