Perioperative Treatment of Gastrointestinal Stromal Tumors
By Gustavo Dos Santos Fernandes, MD1, Charles D. Blanke, MD2, Daniela Freitas, MD3, Rodrigo Guedes, MD4, Paulo M. Hoff, MD5 |
January 1, 2009
1Medical Oncology Fellow, Centro de Oncologia, Hospital Sírio-Libanês
2Professor of Medicine, British Columbia Cancer Agency, and University of British Columbia, Vancouver, BC, Canada
3Associate Member, Centro de Oncologia, Hospital Sírio-Libanês
4Medical Oncology Fellow, Centro de Oncologia, Hospital Sírio-Libanês
5Executive Director, Centro de Oncologia, Hospital Sírio-Libanês, Medical Oncology, University of São Paulo, São Paulo, Brazil
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(Drug information on 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.
Case Reports of Neoadjuvant Imatinib in GIST
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.
Mentioned in This Article
Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.
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.
1. Fletcher CD, Berman JJ, Corless C, et al: Diagnosis of gastrointestinal stromal tumors: A consensus approach. Int J Surg Pathol 10:81-89, 2002.
2. Mazur MT, Clark HB: Gastric stromal tumors. Reappraisal of histogenesis. Am J Surg Pathol 7:507-519, 1983.
3. Nishida T, Hirota S, Taniguchi M, et al: Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet 19:323-324, 1998.
4. Hirota S, Isozaki K, Moriyama Y, et al: Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577-580, 1998.
5. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003.
6. van Oosterom AT, Verweij J: New drugs for the treatment of sarcomas. Hematol Oncol Clin North Am 9:909-925, 1995.
7. Joensuu H: Gastrointestinal stromal tumor (GIST). Ann Oncol 17(suppl 10):x280-286, 2006.
8. Tryggvason G, Gislason HG, Magnusson MK, et al: Gastrointestinal stromal tumors in Iceland, 1990-2003: The Icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer 117:289-293, 2005.
9. Nilsson B, Bumming P, Meis-Kindblom JM, et al: Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden. Cancer 103:821-829, 2005.
10. Kawanowa K, Sakuma Y, Sakurai S, et al: High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol 37:1527-1535, 2006.
11. Tran T, Davila JA, El-Serag HB: The epidemiology of malignant gastrointestinal stromal tumors: An analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol 100:162-168, 2005.
12. DeMatteo RP, Gold JS, Saran L, et al: Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer 112:608-615, 2008.
13. Miettinen M, Sobin LH, Lasota J: Gastrointestinal stromal tumors of the stomach: A clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 29:52-68, 2005.
14. Miettinen M, Makhlouf H, Sobin LH, et al: Gastrointestinal stromal tumors of the jejunum and ileum: A clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol 30:477-489, 2006.
15. Miettinen M, Lasota J: Gastrointestinal stromal tumors: Pathology and prognosis at different sites. Semin Diagn Pathol 23:70-83, 2006.
16. Emory TS, Sobin LH, Lukes L, et al: Prognosis of gastrointestinal smooth-muscle (stromal) tumors: Dependence on anatomic site. Am J Surg Pathol 23:82-87, 1999.
17. Huang HY, Li CF, Huang WW, et al: A modification of NIH consensus criteria to better distinguish the highly lethal subset of primary localized gastrointestinal stromal tumors: A subdivision of the original high-risk group on the basis of outcome. Surgery 141:748-756, 2007.
18. Fletcher CD, Berman JJ, Corless C, et al: Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 33:459-465, 2002.
19. Kantarjian H, Sawyers C, Hochhaus A, et al: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645-652, 2002.
20. Druker BJ, Guilhot F, O’Brien SG, et al: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408-2417, 2006.
21. Tuveson DA, Willis NA, Jacks T, et al: STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: Biological and clinical implications. Oncogene 20:5054-5058, 2001.
22. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052-1056, 2001.
23. van Oosterom AT, Judson I, Verweij J, et al: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: A phase I study. Lancet 358:1421-1423, 2001.
24. Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002.
25. Blanke CD, Demetri GD, von Mehren M, et al: Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26:620-625, 2008.
26. Blay JY, Le Cesne A, Ray-Coquard I, et al: Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: The French Sarcoma Group. J Clin Oncol 25:1107-1113, 2007.
27. Blanke CD, Rankin C, Demetri GD, et al: Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26:626-632, 2008.
28. Zalcberg JR, Verweij J, Casali PG, et al: Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 41:1751-1757, 2005.
29. Van Glabbeke MM, Owzar K, Rankin C, et al: Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): A meta-analyis based on 1,640 patients (pts) (abstract 10004). J Clin Oncol 25(18S):546s, 2007.
30. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003.
31. Heinrich MC, Corless CL, Blanke CD, et al: Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24:4764-4774, 2006.
32. Verweij J, Casali PG, Zalcberg J, et al: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 364:1127-1134, 2004.
33. Debiec-Rychter M, Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093-1103, 2006.
34. Patel S, Zalcberg JR: Optimizing the dose of imatinib for treatment of gastrointestinal stromal tumours: Lessons from the phase 3 trials. Eur J Cancer 44:501-509, 2008.
35. Corless CL, Schroeder A, Griffith D, et al: PDGFRA mutations in gastrointestinal stromal tumors: Frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23:5357-5364, 2005.
36. Husband JE, Schwartz LH, Spencer J, et al: Evaluation of the response to treatment of solid tumours—a consensus statement of the International Cancer Imaging Society. Br J Cancer 90:2256-2260, 2004.
37. Antoch G, Kanja J, Bauer S, et al: Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 45:357-365, 2004.
38. Stroobants S, Goeminne J, Seegers M, et al: 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer 39:2012-2020, 2003.
39. Choi H, Charnsangavej C, Faria SC, et al: Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: Proposal of new computed tomography response criteria. J Clin Oncol 25:1753-1759, 2007.
40. Benjamin RS, Choi H, Macapinlac HA, et al: We should desist using RECIST, at least in GIST. J Clin Oncol 25:1760-1764, 2007.
41. Buemming P, Meis-Kindblom JM, Kindblom LG, et al: Is there an indication for adjuvant treatment with imatinib mesylate in patients with aggressive gastrointestinal stromal tumors (GISTs) (abstract 3289)? Proc Am Soc Clin Oncol 22:818, 2003.
42. Nilsson BE, Bumming P, Meis-Kindblom JM, et al: Treatment of gastrointestinal stromal tumors GISTs) with imatinib in neoadjuvant, adjuvant and palliative settings, a centre-based study of 17 patients (abstract 3337). Proc Am Soc Clin Oncol 22:830, 2003.
43. Dematteo RP, Antonescu CR, Chadaram V, et al: Adjuvant imatinib mesylate in patients with primary high risk gastrointestinal stromal tumor (GIST) following complete resection: Safety results from the U.S. Intergroup Phase II trial ACOSOG Z9000 (abstract 9009). J Clin Oncol 23:818s, 2005.
44. DeMatteo RP, Owzar K, Antonescu CR, et al: Efficacy of adjuvant imatinib mesylate following complete resection of localized, primary gastrointestinal stromal tumor (GIST) at high risk of recurrence: The U.S. Intergroup phase II trial ACOSOG Z9000 (abstract 8). Presented at the 2008 Gastrointestinal Cancers Symposium; Orlando, Fla; Jan 25-27, 2008.
45. Zhan WH, for the China Gastrointestinal Cooperative Group: Efficacy and safety of adjuvant post-surgical therapy with imatinib in patients with high risk of relapsing GIST (abstract 10045). J Clin Oncol 25:556s, 2007.
46. DeMatteo R, Owzar K, Maki R, et al: Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup phase III trial ACOSOG Z9001 (abstract 10079). Presented at the Annual Meeting of the American Society of Clinical Oncology, Chicago, June 1-5, 2007. Available at www.asco.org. Accessed December 4, 2008.
47. Gold JS, Dematteo RP: Combined surgical and molecular therapy: The gastrointestinal stromal tumor model. Ann Surg 244:176-184, 2006.
48. Hasegawa J, Kanda T, Hirota S, et al: Surgical interventions for focal progression of advanced gastrointestinal stromal tumors during imatinib therapy. Int J Clin Oncol 12:212-217, 2007.
49. Bonvalot S, Eldweny H, Pechoux CL, et al: Impact of surgery on advanced gastrointestinal stromal tumors (GIST) in the imatinib era. Ann Surg Oncol 13:1596-1603, 2006.
50. DeMatteo RP, Maki RG, Singer S, et al: Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor. Ann Surg 245:347-352, 2007.
51. Rutkowski P, Nowecki Z, Nyckowski P, et al: Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 93:304-311, 2006.
52. Raut CP, Posner M, Desai J, et al: Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24:2325-2331, 2006.
53. Al-Batran SE, Hartmann JT, Heidel F, et al: Focal progression in patients with gastrointestinal stromal tumors after initial response to imatinib mesylate: A three-center-based study of 38 patients. Gastric Cancer 10:145-152, 2007.
54. Andtbacka RH, Ng CS, Scaife CL, et al: Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol 14:14-24, 2007.
55. Pantaleo MA, Di Battista M, Catena F, et al: Surgical debulking of gastrointestinal stromal tumors: Is it a reasonable option after second-line treatment with sunitinib? J Cancer Res Clin Oncol 134:625-630, 2008.
56. Joensuu H: Sunitinib for imatinib-resistant GIST. Lancet 368:1303-1304, 2006.
57. Scaife CL, Hunt KK, Patel SR, et al: Is there a role for surgery in patients with “unresectable” cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate? Am J Surg 186:665-669, 2003.
58. Eisenberg BL, Harris J, Blanke C, et al: Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and recurrent operable GI stromal tumor (GIST)—early results of RTOG 0132 (abstract 80). Presented at the Society of Surgical Oncology’s 61st Annual Cancer Symposium; Chicago; March 13-16, 2008.
59. de Vos tot Nederveen Cappel RJ, van Hillegersberg R, Rodenhuis S, et al: Downstaging of an advanced gastrointestinal stromal tumor by neoadjuvant imatinib. Dig Surg 21:77-79, 2004.
60. Katz D, Segal A, Alberton Y, et al: Neoadjuvant imatinib for unresectable gastrointestinal stromal tumor. Anticancer Drugs 15:599-602, 2004.
61. Cavaliere D, Vagliasindi A, Mura G, et al: Downstaging of a gastric GIST by neoadjuvant imatinib and endoscopic assisted laparoscopic resection. Eur J Surg Oncol 33:1044-1046, 2007.
62. Shah JN, Sun W, Seethala RR, et al: Neoadjuvant therapy with imatinib mesylate for locally advanced GI stromal tumor. Gastrointest Endosc 61:625-627, 2005.
63. Gronchi A, Fiore M, Miselli F, et al: Surgery of residual disease following molecular-targeted therapy with imatinib mesylate in advanced/metastatic GIST. Ann Surg 245:341-346, 2007.
64. Loughrey MB, Mitchell C, Mann GB, et al: Gastrointestinal stromal tumour treated with neoadjuvant imatinib. J Clin Pathol 58:779-781, 2005.