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Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 4, pp 715–723 | Cite as

New fronts in the adjuvant treatment of GIST

  • Peter ReichardtEmail author
  • Heikki Joensuu
  • Jean-Yves Blay
Review Article

Abstract

Purpose

To review the prognostic factors and stratification systems used to determine the need for adjuvant therapy in the treatment of gastrointestinal stromal tumors (GIST), and to review recent clinical advances in investigation of the efficacy and safety of adjuvant imatinib mesylate treatment.

Methods

Recent data from clinical trials of various durations of adjuvant imatinib in GIST are reviewed, with emphasis on key results from the Phase III American College of Surgeons Oncology Group (ACOSOG) Z9001 trial and the Scandinavian Sarcoma Group XVIII/Arbeitsgemeinschaft Internistische Onkologie (SSGXVIII/AIO) trial.

Results

Complete surgical resection remains the standard of treatment for localized GISTs; however, disease recurrence occurs in up to 50 % of patients who undergo complete resection. The ACOSOG Z9001 trial established that 1 year of adjuvant imatinib reduces the risk of recurrence in patients with resected GIST. The SSGXVIII/AIO trial further demonstrated that 3-year adjuvant imatinib improves both recurrence-free survival and overall survival compared with 1-year therapy in patients at high risk of recurrence after surgery. Considering risk factors associated with tumor recurrence is essential for identifying the patients who are most likely to benefit from adjuvant imatinib.

Conclusions

Although the optimal duration of adjuvant therapy remains to be determined, results from these pivotal trials provide firm evidence that adjuvant imatinib improves recurrence-free survival and improved overall survival of patients in the SSGXVIII/AIO trial. Ongoing studies may shed further light on the benefits and harms of adjuvant therapy, as well as the most appropriate patient candidates for adjuvant imatinib treatment.

Keywords

Gastrointestinal stromal tumor Imatinib Tyrosine kinase inhibitor KIT Metastatic Adjuvant 

Notes

Acknowledgments

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Jared Wels, PhD, for his medical editorial assistance with this manuscript.

References

  1. 1.
    Miettinen M, Sobin LH, Lasota J (2005) 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 29:52–68PubMedCrossRefGoogle Scholar
  2. 2.
    Miettinen M, Makhlouf H, Sobin LH, Lasota J (2006) 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 30:477–489PubMedCrossRefGoogle Scholar
  3. 3.
    National Comprehensive Cancer Center (2012) NCCN clinical practice guidelines in oncology: soft tissue sarcoma V2.2012. http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed 22 Aug 2012
  4. 4.
    Casali PG, Blay JY (2010) Gastrointestinal stromal tumours: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v98–v102PubMedCrossRefGoogle Scholar
  5. 5.
    DeMatteo RP, Lewis JJ, Leung D et al (2000) Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 231:51–58PubMedCrossRefGoogle Scholar
  6. 6.
    Gold JS, Gonen M, Gutierrez A et al (2009) Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol 10:1045–1052PubMedCrossRefGoogle Scholar
  7. 7.
    Maleddu A, Pantaleo MA, Nannini M, Biasco G (2011) The role of mutational analysis of KIT and PDGFRA in gastrointestinal stromal tumors in a clinical setting. J Transl Med 9:75PubMedCrossRefGoogle Scholar
  8. 8.
    Hassan I, You YN, Shyyan R et al (2008) Surgically managed gastrointestinal stromal tumors: a comparative and prognostic analysis. Ann Surg Oncol 15:52–59PubMedCrossRefGoogle Scholar
  9. 9.
    Joensuu H, Vehtari A, Riihimaki J et al (2012) Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 13:265–274PubMedCrossRefGoogle Scholar
  10. 10.
    DeMatteo RP, Heinrich MC, El Rifai WM, Demetri G (2002) Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 33:466–477PubMedCrossRefGoogle Scholar
  11. 11.
    Rutkowski P, Wozniak A, Debiec-Rychter M et al (2011) Clinical utility of the new American Joint Committee on Cancer staging system for gastrointestinal stromal tumors: current overall survival after primary tumor resection. Cancer 117:4916–4924PubMedCrossRefGoogle Scholar
  12. 12.
    Joensuu H, Roberts PJ, Sarlomo-Rikala M et al (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056PubMedCrossRefGoogle Scholar
  13. 13.
    Demetri GD, von Mehren M, Blanke CD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480PubMedCrossRefGoogle Scholar
  14. 14.
    Eisenberg BL, Trent JC (2011) Adjuvant and neoadjuvant imatinib therapy: current role in the management of gastrointestinal stromal tumors. Int J Cancer 129:2533–2542PubMedCrossRefGoogle Scholar
  15. 15.
    Buchdunger E, Cioffi CL, Law N et al (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295:139–145PubMedGoogle Scholar
  16. 16.
    Blanke CD, Rankin C, Demetri GD et al (2008) 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 26:626–632PubMedCrossRefGoogle Scholar
  17. 17.
    Cohen MH, Cortazar P, Justice R, Pazdur R (2010) Approval summary: imatinib mesylate in the adjuvant treatment of malignant gastrointestinal stromal tumors. Oncologist 15:300–307PubMedCrossRefGoogle Scholar
  18. 18.
    Joensuu H (2008) Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 39:1411–1419PubMedCrossRefGoogle Scholar
  19. 19.
    Rutkowski P, Bylina E, Wozniak A et al (2011) Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour: the impact of tumour rupture on patient outcomes. Eur J Surg Oncol 37:890–896PubMedCrossRefGoogle Scholar
  20. 20.
    Fletcher CD, Berman JJ, Corless C et al (2002) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33:459–465PubMedCrossRefGoogle Scholar
  21. 21.
    Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 130:1466–1478PubMedGoogle Scholar
  22. 22.
    Rutkowski P, Nowecki ZI, Michej W et al (2007) Risk criteria and prognostic factors for predicting recurrences after resection of primary gastrointestinal stromal tumor. Ann Surg Oncol 14:2018–2027PubMedCrossRefGoogle Scholar
  23. 23.
    Takahashi T, Nakajima K, Nishitani A et al (2007) An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors. Int J Clin Oncol 12:369–374PubMedCrossRefGoogle Scholar
  24. 24.
    Hohenberger P, Ronellenfitsch U, Oladeji O et al (2010) Pattern of recurrence in patients with ruptured primary gastrointestinal stromal tumour. Br J Surg 97:1854–1859PubMedCrossRefGoogle Scholar
  25. 25.
    Rossi S, Miceli R, Messerini L et al (2011) Natural history of imatinib-naive GISTs: a retrospective analysis of 929 cases with long-term follow-up and development of a survival nomogram based on mitotic index and size as continuous variables. Am J Surg Pathol 35:1646–1656PubMedCrossRefGoogle Scholar
  26. 26.
    DeMatteo RP, Ballman KV, Antonescu CR et al (2009) Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373:1097–1104PubMedCrossRefGoogle Scholar
  27. 27.
    DeMatteo RP, Owzar K, Antonescu CR et al (2008) Efficacy of adjuvant imatinib mesylate following complete resection of localized, primary gastrointestinal stromal tumor (GIST) at high risk of recurrence: the US Intergroup phase II trial ACOSOG Z9000. ASCO 2008 Gastrointestinal Cancers Symposium (Abstract 8)Google Scholar
  28. 28.
  29. 29.
    Li J, Gong JF, Wu AW, Shen L (2011) Post-operative imatinib in patients with intermediate or high risk gastrointestinal stromal tumor. Eur J Surg Oncol 37:319–324PubMedCrossRefGoogle Scholar
  30. 30.
    Kang B Sr, Lee J, Ryu M et al (2009) A phase II study of imatinib mesylate as adjuvant treatment for curatively resected high-risk localized gastrointestinal stromal tumors. J Clin Oncol (Meeting Abstracts) 27:e21515Google Scholar
  31. 31.
    Joensuu H, Eriksson M, Sundby HK et al (2012) One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 307:1265–1272PubMedCrossRefGoogle Scholar
  32. 32.
    Casali PG, Le Cesne A, Velasco AP et al (2013) Imatinib failure-free survival (IFS) in patients with localized gastrointestinal stromal tumors (GIST) treated with adjuvant imatinib (IM): The EORTC/AGITG/FSG/GEIS/ISG randomized controlled Phase III trial. J Clin Oncol (Meeting Abstracts) 31:10500Google Scholar
  33. 33.
    ClinicalTrials.gov (2012) Five year adjuvant imatinib mesylate (Gleevec®) in gastrointestinal stromal tumor (GIST). ClinicalTrials.gov website. http://clinicaltrials.gov/ct2/show/NCT00867113. Accessed 6 Feb 2013
  34. 34.
    Jiang WZ, Guan GX, Lu HS et al (2011) Adjuvant imatinib treatment after R0 resection for patients with high-risk gastrointestinal stromal tumors: a median follow-up of 44 months. J Surg Oncol 104:760–764PubMedCrossRefGoogle Scholar
  35. 35.
    Corless CL, Ballman KV, Antonescu C et al (2010) Relation of tumor pathologic and molecular features to outcome after surgical resection of localized primary gastrointestinal stromal tumor (GIST): results of the intergroup phase III trial ACOSOG Z9001. J Clin Oncol (Meeting Abstracts) 28:10006Google Scholar
  36. 36.
    Lasota J, vel Dobosz AJ, Wasag B et al (2007) Presence of homozygous KIT exon 11 mutations is strongly associated with malignant clinical behavior in gastrointestinal stromal tumors. Lab Invest 87:1029–1041PubMedCrossRefGoogle Scholar
  37. 37.
    Corless CL, Heinrich MC (2008) Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol 3:557–586PubMedCrossRefGoogle Scholar
  38. 38.
    Heinrich MC, Corless CL, Demetri GD et al (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349PubMedCrossRefGoogle Scholar
  39. 39.
    Debiec-Rychter M, Sciot R, Le Cesne A et al (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093–1103PubMedCrossRefGoogle Scholar
  40. 40.
    Corless CL, Schroeder A, Griffith D et al (2005) PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23:5357–5364PubMedCrossRefGoogle Scholar
  41. 41.
    Weisberg E, Wright RD, Jiang J et al (2006) Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. Gastroenterology 131:1734–1742PubMedCrossRefGoogle Scholar
  42. 42.
    Cassier P, Fumagalli E, Rutkowski P et al (2012) Outcome of patients with platelet derived growth factor receptor alpha-mutated GIST in the tyrosine kinase inhibitor era. Clin Cancer Res 18:4458–4464PubMedCrossRefGoogle Scholar
  43. 43.
    Lamba G, Gupta R, Lee B, Ambrale S, Liu D (2012) Current management and prognostic features for gastrointestinal stromal tumor (GIST). Exp Hematol Oncol 1:14PubMedCrossRefGoogle Scholar
  44. 44.
    Joensuu H, Hohenberger P, Corless CL (2013) Gastrointestinal stromal tumour. Lancet [Epub ahead of print]Google Scholar
  45. 45.
    Blay JY, Le Cesne A, Ray-Coquard I et al (2007) 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 25:1107–1113PubMedCrossRefGoogle Scholar
  46. 46.
    Le Cesne A, Ray-Coquard I, Bui BN et al (2010) 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 11:942–949PubMedCrossRefGoogle Scholar
  47. 47.
    Ray-Coquard IL, Bin Bui N, Adenis A et al (2010) Risk of relapse with imatinib (IM) discontinuation at 5 years in advanced GIST patients: results of the prospective BFR14 randomized phase III study comparing interruption versus continuation of IM at 5 years of treatment: A French Sarcoma Group Study. J Clin Oncol (Meeting Abstracts) 28:10032Google Scholar
  48. 48.
    Le Cesne A, Ray-Coquard IL, Bui Nguyen B et al (2011) Time to secondary resistance (TSR) after interruption of imatinib (IM) in advanced GIST: updated results of the prospective French Sarcoma Group randomized phase III trial on long-term survival. J Clin Oncol 29:10015Google Scholar
  49. 49.
    Domont J, Blay J, Ray-Coquard IL et al (2011) Influence of imatinib interruption and imatinib rechallenge on the residual tumor volume in patients with advanced GIST: result of the BFR14 prospective French Sarcoma Group randomized phase III trial. J Clin Oncol 29:10054Google Scholar
  50. 50.
    Reichardt P, Hartmann J, Sundby Hall K et al (2011) Response to imatinib rechallenge of GIST that recurs following completion of adjuvant imatinib treatment: the first analysis in the SSGXVIII/AIO trial patient population. Eur J Cancer 45:31LBAGoogle Scholar
  51. 51.
    Le Cesne A, Ray-Coquard I, Bin Bui N et al (2010) Time to onset of progression after imatinib interruption and outcome of patients with advanced GIST: results of the BFR14 prospective French Sarcoma Group randomized phase III trial. J Clin Oncol (Meeting Abstracts) 28:10033Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Peter Reichardt
    • 1
    Email author
  • Heikki Joensuu
    • 2
  • Jean-Yves Blay
    • 3
  1. 1.Department of Hematology, Oncology and Palliative MedicineHELIOS Klinikum Bad SaarowBad SaarowGermany
  2. 2.Department of OncologyHelsinki University Central HospitalHelsinkiFinland
  3. 3.Department of Medical OncologyCentre Léon-BérardLyonFrance

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