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Journal of Clinical Oncology, Vol 24, No 15 (May 20), 2006: pp. 2325-2331 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.3439 Surgical Management of Advanced Gastrointestinal Stromal Tumors After Treatment With Targeted Systemic Therapy Using Kinase InhibitorsFrom the Departments of Surgery, Anesthesia, Medical Oncology, Biostatistics and Computational Biology, and Pathology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA Address reprint requests to Monica M. Bertagnolli, MD, Brigham and Women's Hospital, Department of Surgery, 75 Francis St, Boston, MA 02115; e-mail: mbertagnolli{at}partners.org
Purpose While targeted inhibitors of tyrosine kinase activity demonstrate dramatic efficacy in the majority of patients with advanced gastrointestinal stromal tumors (GISTs), cure remains elusive and resistance to systemic therapy is a challenge. To assess the role of surgery in multimodality management of GISTs, we studied postoperative outcomes in patients treated with targeted kinase inhibitors for advanced GIST. Methods We evaluated outcomes in a single institution series of 69 consecutive patients who underwent surgery for advanced GISTs while receiving kinase inhibitors. Patients were categorized based on extent of disease before surgery (stable disease, limited disease progression, generalized disease progression) and surgical result (no evidence of disease, minimal residual disease, bulky residual disease). Results Disease status before surgery was associated with surgical result (P < .0001; median follow-up, 14.6 months). After surgery, there was no evidence of disease in 78%, 25%, and 7% of patients with stable disease, limited progression, and generalized progression, respectively. Bulky residual disease remained after surgery in 4%, 16%, and 43% of the patients with stable disease, limited progression, and generalized progression. Twelve-month progression-free survival was 80%, 33%, and 0% for patients with stable disease, limited progression, and generalized progression (P < .0001). Twelve-month overall survival was 95%, 86%, and 0% for patients with stable disease, limited progression, and generalized progression (P < .0001). Conclusion Patients with advanced GISTs exhibiting stable disease or limited progression on kinase inhibitor therapy have prolonged overall survival after debulking procedures. Surgery has little to offer in the setting of generalized progression.
Gastrointestinal stromal tumors (GISTs) are an uncommon malignancy of the gastrointestinal (GI) tract, accounting for only 0.2% of all GI malignancies. However, they are the most common sarcoma of the abdomen.1 Primary GISTs arise throughout the GI tract, most commonly in the stomach (40% to 70%), followed by small bowel (20% to 40%), colon and rectum (5% to 15%), and esophagus (< 5%).2,3 GISTs exhibit a broad spectrum of clinical behavior, with some low-risk lesions remaining stable for years, while others progress rapidly to widely metastatic disease.1,4 Many GISTs are asymptomatic, discovered incidentally during imaging or at laparotomy for unrelated reasons. Between 15% and 50% of GISTs are metastatic at the time of diagnosis.2,5 Approximately 85% of GISTs express the CD117 antigen, part of the KIT receptor tyrosine kinase.1 In 1998, Hirota et al6 identified gain-of-function mutations of the KIT proto-oncogene in the majority of GISTs. Similar activating mutations have been identified in a related receptor tyrosine kinase, platelet-derived growth factor receptor-alpha (PDGFRA).7 Before 2001, surgery was the only effective treatment for GISTs. Five-year survival rates for patients with GISTs ranged from 28% to 80%.4,8-10 In approximately 50% of patients, complete resection was not possible, and median survival ranged from 10 months to 23 months.4,9 Patients treated before 2001 achieved little benefit from chemotherapy or radiation therapy. Dramatic improvement in GIST management occurred with the recognition that mutational activation of KIT or PDGFRA stimulated growth of these cancer cells. This led to effective systemic therapies in the form of small molecule inhibitors, such as imatinib mesylate (Gleevec; Novartis Pharma, Basel, Switzerland) or sunitinib malate (SU11248; Sutent, Pfizer Inc, New York, NY). These agents block signaling via KIT or PDGFRA by binding to the adenosine triphosphate-binding pocket required for phosphorylation and activation. In 2002, a large, multicenter trial of imatinib for patients with metastatic GIST demonstrated partial responses in 54%, stable disease in 28%, and disease progression in 14%.11 Imatinib was approved for treatment of metastatic or unresectable GISTs in February 2002.12 Phase I/II and III studies have shown that sunitinib demonstrates antitumor efficacy in patients resistant to imatinib.13,14 Sunitinib was approved for treatment of metastatic or unresectable GISTs in January, 2006.15 Surgery traditionally played a palliative role for patients with metastatic or locally advanced GISTs. For patients with indolent disease, debulking large lesions that produced significant pain or symptoms was beneficial. Patients with a good performance status also benefited from surgery to control tumor-associated bleeding, intestinal perforation, or fistula formation. The advent of effective therapy targeting the underlying molecular pathophysiology of GISTs through the mutationally activated kinase oncoproteins dramatically altered the natural history of advanced disease. Imatinib and sunitinib are relatively well tolerated compared with traditional chemotherapeutic agents, and most patients maintain an excellent performance status in the setting of stable or limited progression disease.11,14,16 With these recent changes in the management of advanced GISTs, it is now critical to reassess the role of surgery. Surgical resection following imatinib or sunitinib therapy may be curative in some patients with advanced disease. By resecting clones of disease that have acquired drug resistance, surgical debulking may prolong survival in patients with metastatic disease, as long as the remaining disease remains drug responsive. This report documents the results of surgery performed in patients with unresectable or metastatic GISTs treated with imatinib and/or sunitinib.
Patient Selection and Preoperative Management This retrospective study was approved by the institutional review boards of the Brigham and Women's Hospital and the Dana-Farber/Partners Cancer Center (Boston, MA). A consecutive series of 69 patients with advanced GISTs (unresectable primary disease or metastatic disease) undergoing surgery for disease management between March 2002 and November 2004 was reviewed. These patients were referred to the sarcoma service at the Dana-Farber Cancer Institute and Brigham and Women's Hospital, where their care was managed by a multidisciplinary team, including three medical oncologists (J.A.M., S.G., G.D.D.) and two surgical oncologists (M.M.B., C.P.R.). Patient demographic data are listed in Table 1. Before surgery, the patient's diagnosis was confirmed by review of tumor pathology by a single senior pathologist (C.D.M.F.). Immunostaining for c-KIT was positive in 68 of the 69 patients (99%). The single patient whose GIST did not express c-KIT had an unresectable primary pelvis tumor that responded to preoperative treatment with imatinib.
Preoperative agents are listed in Table 2. Patients generally received systemic therapy with either imatinib (45 patients; 65%) or, if experiencing disease progression while on imatinib, sunitinib as part of a phase I/II clinical trial (21 patients; 30%). One patient was treated with imatinib and doxorubicin. Two patients with stable disease were not on imatinib or sunitinib at the time of surgery.
All decisions to proceed with surgery were made jointly by the treating surgeon and medical oncologist. Indications for surgery were described by three clinical categories, which were documented by the treating physicians before surgery. The first category, stable disease, included patients initially presenting with unresectable primary disease or metastatic GIST who achieved a drug response significant enough to render their disease resectable. No patients in this category demonstrated tumor progression before surgery. The operating surgeon confirmed that all disease could be resected based on preoperative computed tomography imaging. The second category included patients with limited progression disease while undergoing treatment with imatinib and/or sunitinib. In these patients, multiple sites of disease were present such that complete tumor resection was not possible. The majority of disease was either radiographically stable or responding to drug therapy, and importantly, all sites of disease progression could be resected. The third category, generalized disease progression, included patients with metastatic GIST whose disease was progressing in multiple sites, and in whom, in the opinion of the surgeon, complete resection of all progressing disease sites would not be possible. Of the 14 patients undergoing surgery in the setting of generalized disease progression, six patients (43%) underwent surgery for emergency indications, including intestinal perforation, bleeding, or intratumoral abscess formation. The indications for surgery in the other eight patients were symptomatic progression of tumors on imatinib (n = 3) and radiographic progression of imatinib-resistant tumors on sunitinib (n = 5).
Conduct of Surgery
Postoperative Management
End Points and Statistics PFS and OS percentages, standard errors, and treatment effect comparisons were obtained from the Kaplan-Meier method,17 Greenwood's formula,18 and log-rank test,19 respectively. Two-sided P values less than or equal to 0.05 were considered statistically significant. No adjustment was made for performing multiple tests. Associations between categoric variables were assessed by a Fisher's exact test.20 The Jonckheere-Terpstra test was used to assess statistical significance for ordered differences in response among classes.21
Demographic data and indications for surgery are presented in Table 1. Of 69 patients, 23 patients (33%) had stable disease before surgery, 32 patients (47%) had limited disease progression, and 14 patients (20%) had generalized disease progression. After surgery, 27 patients (39%) were classified as NED; 30 patients (43%) had minimal residual disease; and 12 patients (17%) had bulky residual disease. Ten patients (14%) required emergency surgery for intestinal perforation, gastrointestinal bleeding, and intratumoral abscess. Four of these patients had limited disease progression and six patients had generalized disease progression before emergency surgery. Surgical procedures performed are listed in Table 3. The most common procedures were bowel resections, with or without hepatic metastectomy. Removal of multiple omental or peritoneal tumor nodules by omentectomy or limited peritoneal stripping was performed in 43 patients (62%). The overall 30-day postoperative complication rate was 33% (Table 4). Two patients required reoperation for postoperative bleeding. Two patients were re-explored for early anastomotic leaks after gastrectomy. Enterocutaneous, rectovaginal, and ureterocolic fistulae were each observed after proctectomy with coloanal anastomosis. An enterocutaneous fistula was observed after small bowel resection secondary to perforation in the setting of generalized disease progression with bulky residual disease. There were no perioperative deaths.
Surgical Outcomes Surgical outcome correlated strongly with the disease status of the patient before surgery (Table 5; P < .0001). Following surgery, there was no evidence of disease in 78% of the patients with stable disease before surgery, 25% of patients with limited disease progression, and 7% of patients with generalized disease progression. Bulky residual disease remained following surgery in 4%, 16%, and 43% of the patients with stable disease, limited disease progression, and generalized disease progression, respectively.
Progression-Free Survival Analysis using the Kaplan-Meier method demonstrated a statistically significant difference in PFS among the three classifications of disease presentation (Fig 1; P < .0001). The 12-month PFS ± SE for patients with stable disease and limited disease progression was 80% ± 9% and 33% ± 9%, respectively. All of the patients presenting with generalized disease progression demonstrated additional disease progression within 12 months of surgery (Table 6). The median time to progression for patients with limited disease progression and generalized disease progression was 7.7 months and 2.9 months, respectively; the PFS curve for patients with stable disease has not yet reached the median. There was a significant difference in PFS between patients with stable disease and limited disease progression (P = .002) and between patients with limited disease progression and generalized disease progression (P < .0001).
OS Kaplan-Meier OS curves illustrate a statistically significant difference in OS among the three classifications of disease presentation (Fig 2; P < .0001). The 12-month OS ± SE for patients with stable disease and limited disease progression was 95% ± 5% and 86% ± 6%, respectively (Table 6). All of the patients presenting with generalized progression of their disease died within 12 months of surgery. The median time to death for patients with limited disease progression and generalized disease progression was 29.8 months and 5.6 months, respectively. Estimating the median time to death for patients with limited disease progression was only possible due to the occurrence of one death more than 25 months after surgery. The OS curve for patients with stable disease has not yet reached the median. There was no significant difference in OS between patients with stable disease and limited disease progression (P = .22). Patients with limited disease progression experienced significantly better OS than those with generalized disease progression (P < .0001).
Sensitivity Analysis Of the 14 patients with generalized disease progression undergoing surgery, six patients (43%) had emergency indications, including intestinal perforation, hemorrhage, or intratumoral abscess formation. These six patients had worse outcomes when compared with the eight patients who underwent elective surgery. Postoperatively, the six patients needing emergency surgery were NED (n = 1) or had minimal (n = 1) or bulky (n = 4) residual disease; the eight patients undergoing elective surgery had minimal (n = 6) or bulky (n = 2) residual disease. The median time to progression for patients with generalized disease progression was 3.2 months after elective surgery (n = 8) and 1.7 months after emergency surgery (n = 6; P = .006). Their median time to death was 5.9 months after elective surgery and 4.9 months after emergency surgery (P = .23). As a result of these differences, we performed a sensitivity analysis (excluding the six cases requiring emergency surgery) and reanalyzed the data. Disease presentation before surgery was again strongly associated with the surgical result. There was a statistically significant difference in PFS and OS comparing patients with limited disease progression with those with generalized disease progression (P = .0005 and P < .0001, respectively). These survival curves are not shown.
Time to Progression in the Setting of Stable Disease
Imatinib therapy as first-line systemic treatment produces disease regression or stabilization in approximately 80% of patients with advanced GISTs, and sunitinib can achieve antitumor responses in imatinib-refractory GISTs.11,14 However, response to kinase-directed therapy is not maintained indefinitely, and the majority of patients receiving this therapy develop disease progression due to molecular evolution of resistant clones. In patients receiving first-line therapy with imatinib, secondary drug resistance is often characterized by the acquisition of additional activating KIT or PDGFRA mutations in tumor clones, rendering imatinib ineffective.22-24The clinical pattern of disease progression varies among patients, reflecting the clonal evolution of metastatic GISTs. Some patients experience generalized disease progression, similar to that seen with primary drug resistance. Once this develops, individuals have a poor prognosis, with a median survival of approximately 38 weeks.25 Another type of progression, more common in our series, is of a more limited nature, characterized by progressive growth in isolated lesions but drug responsiveness in most tumor deposits. Continued drug therapy likely alters the natural history of limited progression disease, as rapid generalized tumor growth has been observed on discontinuation of drug therapy in this setting. This supports continuing drug therapy in patients with responding or stable tumor clones.26 The majority of patients included in this series were selected for surgical debulking either to remove disease before secondary resistance developed or to halt disease progression by eliminating resistant clones. The primary goal of surgery was to prolong PFS for patients who enjoyed excellent performance status on imatinib or sunitinib therapy. Patients with stable disease on imatinib who underwent surgery had a 12-month PFS of 80% ± 9% after surgery and a 24-month PFS of 88% ± 8% after the start of imatinib therapy. It is impossible to assess the specific contribution of surgery to the survival rates in this series. A randomized clinical trial in patients with advanced GISTs demonstrating disease stability or response to systemic therapy would be reasonable to conduct in order to determine whether kinase-directed therapy followed by early complete surgical resection of all disease is associated with improved outcomes (longer PFS or OS) when compared with kinase-directed therapy without early surgery. For patients with limited disease progression, surgical debulking combined with kinase-directed therapy resulted in a median postoperative PFS of 7.7 months and OS of 29.8 months. Thus, patients with limited disease progression may benefit from debulking procedures by prolonging PFS, particularly if surgery achieves either complete extirpation of all tumors or reduction in tumor burden such that no individual nodule is greater than 1 cm in diameter. At present, most patients with disease progression on imatinib despite dose escalation are managed by altering drug therapy rather than by debulking surgery. Our data suggest that surgery may prolong the effectiveness of first-line systemic therapy with imatinib in patients with advanced GISTs. To confirm this, new clinical trials should be designed to assess the utility of performing surgery at the onset of limited progression, with the potential of delaying the commencement of second-line systemic treatment. Our results indicate that surgery has a very limited role in treating patients with generalized disease progression. There is, however, a significant selection bias in this category of patients, as six of the 14 patients with generalized disease progression underwent surgery for management of life-threatening tumor-associated complications rather than solely to reduce tumor burden. The high acuity of this group is also reflected in their postoperative complication rate of 50%. In conclusion, patients presenting with stable advanced GISTs on KIT-directed therapy experienced prolonged PFS and OS after surgery. Those with limited disease progression usually progressed within 12 months of surgery, but appear to have an improved OS. All patients with generalized progression of metastatic GISTs despite systemic therapy died within 12 months of surgery, and surgery in this setting should be reserved for cases in which a likelihood of significant symptom palliation is high. This study distinguishes which subsets of patients may experience prolonged survival after aggressive treatment with a combination of surgery and kinase-directed therapy. The added benefit of surgery beyond KIT-directed therapy alone in prolonging survival can only be established in prospective trials.
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1 cm in diameter. 
