Annals of Surgical Oncology

, Volume 19, Issue 4, pp 1074–1080 | Cite as

Phase II Trial of Neoadjuvant/adjuvant Imatinib Mesylate for Advanced Primary and Metastatic/recurrent Operable Gastrointestinal Stromal Tumors: Long-term Follow-up Results of Radiation Therapy Oncology Group 0132

  • Dian WangEmail author
  • Qiang Zhang
  • Charles D. Blanke
  • George D. Demetri
  • Michael C. Heinrich
  • James C. Watson
  • John P. Hoffman
  • Scott Okuno
  • John M. Kane
  • Margaret von Mehren
  • Burton L. Eisenberg
Bone and Soft Tissue Sarcomas



Imatinib inhibits the KIT and PDGFR tyrosine kinases, resulting in its notable antitumor activity in gastrointestinal stromal tumor (GIST). We previously reported the early results of a multi-institutional prospective trial (RTOG 0132) using neoadjuvant/adjuvant imatinib either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic/recurrent GIST.


Patients with primary GIST (≥5 cm, group A) or resectable metastatic/recurrent GIST (≥2 cm, group B) received neoadjuvant imatinib (600 mg/day) for approximately 2 months and maintenance postoperative imatinib for 2 years. We have now updated the clinical outcomes including progression-free survival, disease-specific survival, and overall survival at a median follow-up of 5.1 years, and we correlate these end points with duration of imatinib therapy.


Sixty-three patients were originally entered (53 analyzable: 31 in group A and 22 in group B). Estimated 5-year progression-free survival and overall survival were 57% in group A, 30% in group B; and 77% in group A, 68% in group B, respectively. Median time to progression has not been reached for group A and was 4.4 years for group B. In group A, in 7 of 11 patients, disease progressed >2 years from registration; 6 of 7 patients with progression had stopped imatinib before progression. In group B, disease progressed in 10 of 13 patients >2 years from registration; 6 of 10 patients with progressing disease had stopped imatinib before progression. There was no significant increase in toxicity compared with our previous short-term analysis.


This long-term analysis suggests a high percentage of patients experienced disease progression after discontinuation of 2-year maintenance imatinib therapy after surgery. Consideration should be given to studying longer treatment durations in intermediate- to high-risk GIST patients.


Overall Survival Imatinib Imatinib Mesylate Radiation Therapy Oncology Group Imatinib Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Supported in part by grants RTOG U10 CA21661 and CCOP U10 CA37422 from the National Cancer Institute (NCI). The contents of this article are the sole responsibility of the authors and do not necessarily represent the official views of the NCI. The authors received consulting fees, honoraria, and research support as follows: Consulting: Charles D. Blanke (Novartis), George D. Demetri (Novartis), Margaret von Mehren (Novartis), Burt Eisenberg (Novartis), Michael Heinrich (Novartis, MolecularMD). Honoraria: Charles D. Blanke (Novartis), George D. Demetri (Novartis), Michael Heinrich (Novartis), Margaret. von Mehren (Novartis), Burt Eisenberg (Novartis). Research support: George D. Demetri (Novartis), Margaret. von Mehren (Novartis). Michael Heinrich (Novartis, Ariad, Lilly, AROG Pharmaceuticals), Scott Okuno (Novartis). Stock ownership: Michael Heinrich (MolecularMD).


  1. 1.
    Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Network. 2010;8:S1–41.Google Scholar
  2. 2.
    Casali PG, Jost L, Reichardt P, et al. Gastrointestinal stromal tumours: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(Suppl 4):64–7.PubMedGoogle Scholar
  3. 3.
    Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2008;3:557–86.PubMedCrossRefGoogle Scholar
  4. 4.
    Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33:459–65.PubMedCrossRefGoogle Scholar
  5. 5.
    Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708–10.PubMedCrossRefGoogle Scholar
  6. 6.
    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.PubMedCrossRefGoogle Scholar
  7. 7.
    Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9669):1097–104.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    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. 2008;26:620–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364(9440):1127–34.PubMedCrossRefGoogle Scholar
  11. 11.
    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. 2005;41:1751–7.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    Le Cesne A, Van Glabbeke M, Verweij J, et al. Absence of progression as assessed by response evaluation criteria in solid tumors predicts survival in advanced GI stromal tumors treated with imatinib mesylate: the intergroup EORTC-ISG-AGITG phase III trial. J Clin Oncol. 2009;27:3969–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009;99:42–7.PubMedCrossRefGoogle Scholar
  15. 15.
    McAuliffe JC, Hunt KK, Lazar AJ, et al. A randomized, phase II study of preoperative plus postoperative imatinib in GIST: evidence of rapid radiographic response and temporal induction of tumor cell apoptosis. Ann Surg Oncol. 2009;16:910–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York: Wiley, 1980.Google Scholar
  17. 17.
    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457.CrossRefGoogle Scholar
  18. 18.
    Therasse P, Arbuck S, Eisenhauer E, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205–16.PubMedCrossRefGoogle Scholar
  19. 19.
    Blackstein ME, Blay JY, Corless C, et al. Gastrointestinal stromal tumours: consensus statement on diagnosis and treatment. Can J Gastroenterol. 2006;20:157–63.PubMedGoogle Scholar
  20. 20.
    Le Cesne A, Ray-Coquard I, Bui BN, et al. Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. Lancet Oncol. 2010;11:942–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Hassan I, You YN, Shyyan R, et al. Surgically managed gastrointestinal stromal tumors: a comparative and prognostic analysis. Ann Surg Oncol. 2008;15:52–9.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130:1466–78.PubMedGoogle Scholar
  24. 24.
    Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 2008;39:1411–9.PubMedCrossRefGoogle Scholar
  25. 25.
    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. 2008;112:608–15.PubMedCrossRefGoogle Scholar
  26. 26.
    Joensuu H. Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: final results of randomized trial (SSGXVIII/AIO). J Clin Oncol. 2011;(18 Suppl):29.Google Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    Bonvalot S, Eldweny H, Péchoux CL, et al. Impact of surgery on advanced gastrointestinal stromal tumors (GIST) in the imatinib era. Ann Surg Oncol. 2006;13:1596–603.PubMedCrossRefGoogle Scholar
  29. 29.
    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. 2006;93:304–11.PubMedCrossRefGoogle Scholar
  30. 30.
    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. 2006;24:2325–31.PubMedCrossRefGoogle Scholar
  31. 31.
    Blesius A, Cassier PA, Bertucci F, et al. Neoadjuvant IM in patients with locally advanced GIST in the prospective BFR14 trial. BMC Cancer. 2011;11:72.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2011

Authors and Affiliations

  • Dian Wang
    • 1
    Email author
  • Qiang Zhang
    • 2
  • Charles D. Blanke
    • 3
  • George D. Demetri
    • 4
  • Michael C. Heinrich
    • 5
  • James C. Watson
    • 6
  • John P. Hoffman
    • 6
  • Scott Okuno
    • 7
  • John M. Kane
    • 8
  • Margaret von Mehren
    • 6
  • Burton L. Eisenberg
    • 9
  1. 1.Medical College of WisconsinMilwaukeeUSA
  2. 2.Radiation Therapy Oncology Group Statistical CenterPhiladelphiaUSA
  3. 3.University of British Columbia and British Columbia Cancer AgencyVancouverCanada
  4. 4.Dana-Farber Cancer Institute and Harvard Medical SchoolBostonUSA
  5. 5.Portland VA Medical Center and Oregon Health & Science UniversityPortlandUSA
  6. 6.Fox Chase Cancer CenterPhiladelphiaUSA
  7. 7.Mayo ClinicRochesterUSA
  8. 8.Roswell Park Cancer InstituteBuffaloUSA
  9. 9.Dartmouth-Hitchcock Medical CenterLebanonNH

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