A Randomized, Phase II Study of Preoperative plus Postoperative Imatinib in GIST: Evidence of Rapid Radiographic Response and Temporal Induction of Tumor Cell Apoptosis
Gastrointestinal stromal tumor (GIST) is the most common sarcoma arising in the gastrointestinal (GI) tract. Imatinib mesylate (imatinib) is efficacious in treating advanced and metastatic GIST. Patients undergoing resection of GIST realize a highly variable median disease-free survival (DFS). In the absence of prospective data, we conducted a randomized, phase II study to assess the safety and efficacy of preoperative and postoperative imatinib for the treatment of GIST. Nineteen GIST patients undergoing surgical resection were randomized to receive 3, 5, or 7 days of preoperative imatinib (600 mg daily). Patients received postoperative imatinib for 2 years. Perioperative adverse events were compared with those in an imatinib-naïve historical control. The efficacy of imatinib was assessed by 18fluorodeoxyglucose positron emission tomography (18FDG-PET), dynamic computed tomography (dCT), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and DFS. Imatinib did not affect surgical morbidity as compared with an imatinib-naïve cohort (p ≥ 0.1). Most patients responded to preoperative imatinib by 18FDG-PET and dCT (69% and 71%, respectively). Tumor cell apoptosis increased by an average of 12% (range 0–33%) and correlated with the duration of preoperative imatinib (p = 0.04). Median DFS of patients treated with surgery and imatinib was 46 months (range 10–46 months). Tumor size was a predictor of recurrence after postoperative imatinib (p = 0.02). Imatinib appears to be safe and may be considered for patients undergoing surgical resection of their GIST. Radiographic response and tumor cell apoptosis occur within the first week of imatinib therapy.
- Steinert DM, McAuliffe JC, Trent JC. Imatinib mesylate in the treatment of gastrointestinal stromal tumour. Expert Opin Pharmacother. 2005;6:105–13. CrossRef
- Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998;152:1259–69.
- Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80. CrossRef
- Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–10. CrossRef
- Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov. 2002;1:493–502. CrossRef
- Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127–34. CrossRef
- 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. 2008;26:626–32. CrossRef
- DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51–8. CrossRef
- Roberts PJ, Eisenberg B. Clinical presentation of gastrointestinal stromal tumors and treatment of operable disease. Eur J Cancer. 2002;38:S37–8. CrossRef
- Blanke CD, Eisenberg BL, Heinrich MC. Gastrointestinal stromal tumors. Curr Treat Options Oncol. 2001;2:485–91. CrossRef
- Pawlik TM, Vauthey JN, Abdalla EK, et al. Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver. Arch Surg. 2006;141:537–43; discussion 543–4. CrossRef
- Ng EH, Pollock RE, Romsdahl MM. Prognostic implications of patterns of failure for gastrointestinal leiomyosarcomas. Cancer. 1992;69:1334–41. CrossRef
- NCI Na. Common Terminology Criteria For Adverse Events. In: Cancer Therapy Evaluation Program, Edition DCTD, NCI, NIG, DHHS 2003.
- Singer S, Rubin BP, Lux ML, et al. Prognostic value of KIT mutation type, mitotic activity, and histologic subtype in gastrointestinal stromal tumors. J Clin Oncol. 2002;20:3898–905. CrossRef
- Trent JC, Ramdas L, Dupart J, et al. Early effects of imatinib mesylate on the expression of insulin-like growth factor binding protein-3 and positron emission tomography in patients with gastrointestinal stromal tumor. Cancer. 2006;107:1898–908. CrossRef
- Therneau T, Grambsch P. Modeling survival data. New York: Springer; 2000.
- Kaplan E, Meier P. Nonparametric estimator from incomplete observations. J Am Stat Assoc. 1958;53:457–81. CrossRef
- Snedecor G, Cochran W. Statistical methods. Iowa State: University Press; 1980.
- Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–80. CrossRef
- 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. 2006;42:1093–103. CrossRef
- Bidri M, Ktorza S, Vouldoukis I, et al. Nitric oxide pathway is induced by Fc epsilon RI and up-regulated by stem cell factor in mouse mast cells. Eur J Immunol. 1997;27:2907–13. CrossRef
- Van Buren G, 2nd, Camp ER, Yang AD, et al. The role of nitric oxide in mediating tumour blood flow. Expert Opin Ther Targets. 2006;10:689–701. CrossRef
- McAuliffe JLA, Steinert D, Patel S, Benjamin R, Trent J. Kit-stem cell factor (Kit ligand) axis in GIST patients treated with imatinib. American Society of Clinical Oncology Annual Meeting, Edition Chicago, IL, USA; 2007.
- Sihto H, Tynninen O, Bèutzow R, et al. Endothelial cell KIT expression in human tumours. J Pathol. 2007;211:481–8. CrossRef
- Bergers G, Song S, Meyer-Morse N, et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors.[see comment]. J Clin Invest. 2003;111:1287–95.
- Dematteo ROK, Maki R, Pisters P, Blackstein M, Antonescu C, Blanke C, et al. Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrintestinal stromal tumor (GIST): North American Intergroup Phase III trial ACOSOG Z9001. American Society of Clinical Oncology Annual Meeting, Edition Chicago, IL, USA; 2007.
- Andtbacka RH, Ng CS, Scaife CL, et al. Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol. 2007;14:14–24. CrossRef
- 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. 2007;25:1107–13. CrossRef
- Eisenberg BL. Combining imatinib with surgery in gastrointestinal stromal tumors: rationale and ongoing trials. Clin Colorect Cancer. 2006;6:S24–9. CrossRef
- 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. 2001;344:1052–6. CrossRef
- A Randomized, Phase II Study of Preoperative plus Postoperative Imatinib in GIST: Evidence of Rapid Radiographic Response and Temporal Induction of Tumor Cell Apoptosis
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Annals of Surgical Oncology
Volume 16, Issue 4 , pp 910-919
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Industry Sectors
- Author Affiliations
- 1. MD/PhD Program, The University of Texas-Houston, Houston, TX, USA
- 2. Department of Sarcoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Suite FC11.3032, Houston, TX, 77030, USA
- 3. Sarcoma Research Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
- 4. Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
- 5. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
- 6. Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
- 7. Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
- 8. Department of Sarcoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA