This review describes the current multidisciplinary management of gastrointestinal stromal tumor (GIST), which is the most common sarcoma of the gastrointestinal tract. Before 2001, surgery was the only effective therapy for GIST. The discovery of the central role of KIT proto-oncogene mutations in the pathogenesis of this tumor, and the development of specific inhibitors of KIT tyrosine kinase (TK) function, has changed the paradigm of treatment for GISTs. Imatinib and sunitinib are TK inhibitors with activity against GISTs. Their major established role in GIST is in the treatment of advanced disease. A growing body of literature and clinical experience support the potential perioperative use of these drugs. The adjuvant use of imatinib is based on retrospective series and limited prospective studies demonstrating that imatinib reduces the risk of recurrence. Ongoing studies are further defining the length of adjuvant therapy, as well as identifying the patients that could achieve the best results. Neoadjuvant treatment often decreases the tumor size, allowing a less morbid surgery, appears to be safe and beneficial for some patients, and therefore deserves further study.
In contrast to standard adjuvant therapy, neoadjuvant therapy is given before the main (usually surgical) treatment. It is used not only to eliminate circulating tumor cells but also to reduce the size of the tumor, potentially facilitating surgery, and perhaps increasing the chance of organ preservation. Since imatinib results in tumor shrinkage in at least 50% of treated patients,[23,47] its use in the neoadjuvant setting is a logical next step in the development of the drug.
GISTs may present as unresectable disease or as resectable tumors requiring extensive organ disruption. Additionally, recurrence of locally advanced disease remains the norm. Thus, trying to achieve tumor downsizing with imatinib, followed by resection, followed (perhaps) by more imatinib could be an attractive approach. Since 2003, several case reports related to the use of neoadjuvant treatment in GIST have been published (Table 3), and one phase II Intergroup trial has been completed. The usual therapeutic schema involves a short course of imatinib, commonly 3 to 12 months, with frequent imaging studies and reevaluation of the best time for surgery. The decision of when to operate—at first respectability vs after maximum response—remains controversial, particularly since progression can occur rapidly even after a substantial response.
Despite careful patient management, the risk of disease progression is always present, and this possibility should be discussed before the start of treatment, particularly with patients who have borderline-resectable GISTs. In case of progression, a clinical dilemma is established. If radical salvage surgery is possible, it remains a reasonable therapeutic option (as opposed to a salvage systemic therapy, which would likely possess little chance of achieving substantial tumor shrinkage). Unfortunately, the results of surgery are probably worse for more extensive and refractory disease.
Retrospective published data demonstrate that resection of metastatic progressive disease appears to benefit only patients with focal progression, and it has little to offer to those who experience generalized disease progression while receiving imatinib.[48-55] For example, in 69 consecutive patients who underwent surgery for advanced GISTs at Dana-Farber Cancer Institute, 12-month progression-free survival rates were 80%, 33%, and 0%, respectively, for patients who presented before the procedure with stable disease, limited progression, and generalized progression (P < .0001). Overall survival at the same time was also strongly influenced by the presurgical response status, at 95%, 86%, and 0% for patients whose presented with stable disease, limited progression, and generalized progression (P < .0001).
A Memorial Sloan-Kettering series of 13 patients with focal resistance showed similar conclusions: disease progression occurred at a median of 12 months after surgery, and the 2-year overall survival was 36%. In contrast, 7 patients with multifocal resistance showed disease progression at a median of 3 months postoperatively and had a 1-year overall survival rate of 36%. Even if complete, resection does not eliminate the need for continued treatment with imatinib in patients with metastatic disease. Progression-free survival is significantly shorter in patients who discontinue imatinib, as compared to those who continue the drug after resection. In general, treatment of resistant nonsurgical GIST can be approached in different ways. At least two conventional therapeutic strategies can be adapted to this situation: The first alternative is to try to circumvent imatinib resistance by increasing the dose. The second choice is to change the drug, and currently, sunitinib (Sutent) may be the best option in this setting. Despite recent advances with the use of molecular targeted agents, surgical resection remains the only curative therapy for patients with GIST. Although 95% of salvage surgeries for GIST fail, the long-term control obtained with imatinib in a substantial fraction of patients with metastatic disease makes secondary surgery coupled with indefinitely administered imatinib attractive. No prospective trials have tested this approach, but it seems to be safe and may improve patient prognosis.
The role of surgery as part of the treatment plan for metastatic or unresectable GIST in the imatinib era has been explored in a few retrospective series. The group at the Institut Gustave Roussy reviewed results from 180 patients with metastatic or unresectable GIST treated with imatinib, 400 to 800 mg/d, finding that surgical treatment was eventually possible in 22 patients, 5 of whom had nonmetastatic locally advanced disease. The 2-year overall survival rate after surgery was 62%. The median progression-free survival calculated from the initiation of imatinib therapy was 18.7 months for all patients who underwent surgery, and 23.4 months for the 17 patients who had planned surgery. Such data suggest that tumors that become amenable to surgery with the use of imatinib therapy could benefit from secondary surgery.
In 2003, a group at M.D. Anderson Cancer Center published a retrospective study of 126 patients with unresectable c-KIT–positive GIST treated with imatinib prior to surgical resection. They reported that 17 patients had subsequent surgical resections after a median of 10 months of neoadjuvant treatment. Of these patients, 2 had complete pathologic responses, 11 had partial pathologic responses, and 16 underwent complete surgical resection of disease.
In order to strengthen the preliminary data suggesting the benefits of neoadjuvant treatment with imatinib, the Radiation Therapy Oncology Group (RTOG) conducted a phase II trial (RTOG 0132). To be included, patients needed to have a biopsy-proven diagnosis of malignant KIT-positive GIST—either potentially resectable primary disease (≥ 5 cm) or potentially resectable locally recurrent or metastatic disease (≥ 2 cm). Between February and June 2006, 63 patients from 18 institutions were enrolled and treated with preoperative imatinib (600 mg/d) for 8 to 12 weeks, followed by surgical resection and 2 additional years of postoperative imatinib therapy.
Among the 52 patients analyzed, 30 presented with locally advanced disease and 22 presented with recurrent or metastatic disease. The stomach was the primary disease site in 48% of patients; disease in the liver, small bowel, and pelvis accounted for 12%, 10%, and 10% of the cases. The toxicity profile was quite similar to that verified in other trials, with no grade 5 toxicities and 12% grade 4. A surgical procedure was performed in 45 of 52 patients, and only 1 patient died because of an infectious complication.
Among patients who initially presented with locally advanced disease, response to preoperative imatinib (by RECIST criteria) was observed in 2 patients (7%), 25 (83%) achieved stable disease, and none showed disease progression during treatment. Among patients who initially presented with recurrent or metastatic disease, 1 (5%) achieved a partial response and 20 (91%) had stable disease, with only one patient in this group (and the entire trial) showing disease progression during the course of treatment. Within 2 years of follow-up, progression-free and overall survival rates for patients who presented with locally advanced disease were 82% and 93%, respectively. For those with recurrent or metastatic disease, progression-free and overall survival rates were 73% and 91%.
This trial showed that preoperative treatment with imatinib is safe, with a minimal incidence of drug-related toxicity and surgical morbidity. Only one patient had disease progression on treatment, and the majority underwent surgical resection. Progression-free and overall survival are favorable for this group of high-risk patients receiving GIST, especially those with recurrent or metastatic disease. Despite these interesting results, no strong data support the use of neoadjuvant imatinib. This strategy is therefore not recommended outside of a clinical trial. The only reasonable exception would be the use of imatinib by an experienced multidisciplinary team when an objective response could result in organ preservation.
The use of TK inhibitors has resulted in a remarkable improvement in the management of GIST, and the impact of the use of imatinib after surgery seems to be positive. However, it is virtually impossible to draw any firm conclusions about the efficacy of this strategy yet, and well-designed, prospective trials are absolutely necessary. Surgery for residual disease should still be considered an investigational option, despite the growing popularity of this strategy. After changing the paradigm of treatment for metastatic GIST, imatinib mesylate is being increasingly viewed as an option in the adjuvant setting, and possibly in the neoadjuvant treatment of GIST. Ongoing and future trials will need to be conducted and completed before these strategies become the new standard of care for this tumor.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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