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01-01-2013 | Original Article

Two-year adjuvant imatinib mesylate after complete resection of localized, high-risk GIST with KIT exon 11 mutation

Authors: Yoon-Koo Kang, Byung Woog Kang, Seock-Ah Im, Jae-Lyun Lee, Sook Ryun Park, Won Ki Kang, Heung Moon Chang, Tae Won Kim, Do-Youn Oh, Kyung Hae Jung, Min-Hee Ryu

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2013

Abstract

Purpose

To evaluate the efficacy and safety of 2-year adjuvant imatinib for patients at high risk of recurrence after complete resection of localized gastrointestinal stromal tumor with KIT exon 11 mutation.

Methods

Imatinib 400 mg/d was administered until disease recurrence, intolerable toxicities, or for 2 years. The primary end point was recurrence-free survival.

Results

Patients (n = 47) from 4 centers in Korea were enrolled. Treatment was well tolerated. Grade 3–4 toxicities included neutropenia (27.7 %), skin rash (8.5 %), anorexia (4.3 %), and constipation (2.1 %). At a median follow-up of 56.7 months, 19 patients had recurrences. Median recurrence-free survival was 58.9 months, which was significantly longer than 22.7 months from historical data of 27 patients in the pre-imatinib era (P < 0.0001). Imatinib was rechallenged for 15 patients with recurrence after completion of adjuvant imatinib. Thirteen patients had partial response, and two had stable disease. There was only one death so far.

Conclusions

Postoperative adjuvant imatinib for 2 years was safe and could prolong the recurrence-free survival in patients with a high risk of recurrence after complete resection of localized KIT exon 11 mutated gastrointestinal stromal tumor. Reintroduction of imatinib after recurrence appears to be effective if the recurrence develops after completion of adjuvant imatinib.

Nilsson B, Bümming P, Meis-Kindblom JM, Odén A, Dortok A, Gustavsson B, Sablinska K, Kindblom LG (2005) Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden. Cancer 103:821–829PubMedCrossRef

Miettinen M, El-Rifai W, Sobin LH, Lasota J (2002) Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol 33:478–483PubMedCrossRef

Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710PubMedCrossRef

Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580PubMedCrossRef

Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–566PubMedCrossRef

Manley PW, Stiefl N, Cowan-Jacob SW, Kaufman S, Mestan J, Wartmann M, Wiesmann M, Woodman R, Gallagher N (2010) Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib. Bioorg Med Chem 18:6977–6986PubMedCrossRef

Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480PubMedCrossRef

DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF (2000) Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 231:51–58PubMedCrossRef

DeMatteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K, American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team (2009) Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373:1097–1104PubMedCrossRef

10.

Taniguchi M, Nishida T, Hirota S, Isozaki K, Ito T, Nomura T, Matsuda H, Kitamura Y (1999) Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res 59:4297–4300PubMed

11.

Taniguchi M, Nishida T, Hirota S, Isozaki K, Ito T, Nomura T, Matsuda H, Kitamura Y (2004) Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors. Clin Cancer Res 10:3076–3081CrossRef

12.

Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349PubMedCrossRef

13.

Kim TW, Lee H, Kang YK, Choe MS, Ryu MH, Chang HM, Kim JS, Yook JH, Kim BS, Lee JS (2004) Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors. Clin Cancer Res 10:3076–3081PubMedCrossRef

14.

Corless CL, Ballman KV, Antonescu C, Blanke CD, Blackstein ME, Demetri GD, von Mehren M, Maki RG, Pisters PW, DeMatteo RP; American College of Surgeons Oncology Group (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 15 suppl:abstract 10006

15.

Martín J, Poveda A, Llombart-Bosch A, Ramos R, López-Guerrero JA, García del Muro J, Maurel J, Calabuig S, Gutierrez A, González de Sande JL, Martínez J, De Juan A, Laínez N, Losa F, Alija V, Escudero P, Casado A, García P, Blanco R, Buesa JM, Spanish Group for Sarcoma Research (2005) Deletions affecting codons 557–558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol 23:6190–6198PubMedCrossRef

16.

Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, Hibbard MK, Chen CJ, Xiao S, Tuveson DA, Demetri GD, Fletcher CD, Fletcher JA (2001) KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61:8118–8121PubMed

17.

Singer S, Rubin BP, Lux ML, Chen CJ, Demetri GD, Fletcher CD, Fletcher JA (2002) Prognostic value of KIT mutation type, mitotic activity, and histologic subtype in gastrointestinal stromal tumors. J Clin Oncol 20:3898–3905PubMedCrossRef

18.

Andersson J, Bümming P, Meis-Kindblom JM, Sihto H, Nupponen N, Joensuu H, Odén A, Gustavsson B, Kindblom LG, Nilsson B (2006) Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology 130:1573–1581PubMedCrossRef

19.

Wardelmann E, Losen I, Hans V, Neidt I, Speidel N, Bierhoff E, Heinicke T, Pietsch T, Büttner R, Merkelbach-Bruse S (2003) Deletion of Trp-557 and Lys-558 in the juxtamembrane domain of the c-kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors. Int J Cancer 106:887–895PubMedCrossRef

20.

Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, Shiraga S, Bainbridge T, Morich J, Heinrich MC (2005) PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23:5357–5364PubMedCrossRef

21.

Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) (2010) Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol 28:1247–1253CrossRef

22.

Kang HJ, Ryu MH, Kim KM, Park YS, Choi J, Ryoo BY, Kim WH, Im SA, Bang YJ, Park SH, Lee JH, Chung IJ, Bae HI, Kim JG, Lee KH, Song HS, Kwon HC, Baek JH, Shin DB, Lee KE, Kang YK (2011) Imatinib efficacy by tumor genotype in Korean patients with advanced gastrointestinal stromal tumors (GIST): the Korean GIST Study Group (KGSG) study. Acta Oncol. doi:22150077 PubMed

23.

Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23:70–83PubMedCrossRef

24.

Joensuu H, Eriksson M, Hatrmann J, Sundby Hall K, Schutte J, Reichardt A, Schlemmer M, Wardelmann E, Ramadori G, Al-Batran S, Nilsson BE, Monge O, Kallio R, Sarlomo-Rikala M, Bono P, Leinonen M, Hohenberger P, Alvegard T, Reichardt P (2011) Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). J Clin Oncol 29:abstract LBA1

25.

Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, Demetri GD (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056PubMedCrossRef

26.

Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, Blay JY, Leyvraz S, Stul M, Casali PG, Zalcberg J, Verweij J, Van Glabbeke M, Hagemeijer A, Judson I, EORTC Soft Tissue and Bone Sarcoma Group, Italian Sarcoma Group, Australasian GastroIntestinal Trials Group (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093–1103PubMedCrossRef

27.

Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T, Speidel N, Pietsch T, Buettner R, Pink D, Reichardt P, Hohenberger P (2006) Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12:1743–1749PubMedCrossRef

28.

Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880PubMedCrossRef

29.

Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, Town A, McKinley A, Ou WB, Fletcher JA, Fletcher CD, Huang X, Cohen DP, Baum CM, Demetri GD (2008) Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol 26:5352–5359PubMedCrossRef

Title: Two-year adjuvant imatinib mesylate after complete resection of localized, high-risk GIST with KIT exon 11 mutation
Authors: Yoon-Koo Kang
Byung Woog Kang
Seock-Ah Im
Jae-Lyun Lee
Sook Ryun Park
Won Ki Kang
Heung Moon Chang
Tae Won Kim
Do-Youn Oh
Kyung Hae Jung
Min-Hee Ryu
Publication date: 01-01-2013
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-012-1970-3

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