Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial
Ronald P Dematteo, Karla V Ballman, Cristina R Antonescu, Robert G Maki, Peter W T Pisters, George D Demetri, Martin E Blackstein, Charles D Blanke, Margaret von Mehren, Murray F Brennan, Shreyaskumar Patel, Martin D McCarter, Jonathan A Polikoff, Benjamin R Tan, Kouros Owzar, American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team, Ronald P Dematteo, Karla V Ballman, Cristina R Antonescu, Robert G Maki, Peter W T Pisters, George D Demetri, Martin E Blackstein, Charles D Blanke, Margaret von Mehren, Murray F Brennan, Shreyaskumar Patel, Martin D McCarter, Jonathan A Polikoff, Benjamin R Tan, Kouros Owzar, American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team
Abstract
Background: Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor alpha proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour.
Methods: We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197.
Findings: All randomised patients were included in the analysis. At median follow-up of 19.7 months (minimum-maximum 0-56.4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0.35 [0.22-0.53]; one-sided p<0.0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group.
Interpretation: Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour.
Funding: US National Institutes of Health and Novartis Pharmaceuticals.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2915459/bin/nihms108869f1.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2915459/bin/nihms108869f2.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2915459/bin/nihms108869f3a.jpg)
Figure 3
Figure 3A. Recurrence-free survival for…
Figure 3
Figure 3A. Recurrence-free survival for tumor size ≥3 and
Figure 3
Figure 3A. Recurrence-free survival for…
Figure 3
Figure 3A. Recurrence-free survival for tumor size ≥3 and
Figure 4
Overall survival.
Figure 4
Overall survival.
- Adjuvant imatinib in GIST: a self-fulfilling prophecy, or more?Hohenberger P. Hohenberger P. Lancet. 2009 Mar 28;373(9669):1058-60. doi: 10.1016/S0140-6736(09)60562-6. Epub 2009 Mar 18. Lancet. 2009. PMID: 19303138 No abstract available.
- One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial.Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt P. Joensuu H, et al. JAMA. 2012 Mar 28;307(12):1265-72. doi: 10.1001/jama.2012.347. JAMA. 2012. PMID: 22453568 Clinical Trial.
- Approval summary: imatinib mesylate in the adjuvant treatment of malignant gastrointestinal stromal tumors.Cohen MH, Cortazar P, Justice R, Pazdur R. Cohen MH, et al. Oncologist. 2010;15(3):300-7. doi: 10.1634/theoncologist.2009-0120. Epub 2010 Mar 3. Oncologist. 2010. PMID: 20200041 Free PMC article. Clinical Trial.
- Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial.Blay JY, Shen L, Kang YK, Rutkowski P, Qin S, Nosov D, Wan D, Trent J, Srimuninnimit V, Pápai Z, Le Cesne A, Novick S, Taningco L, Mo S, Green S, Reichardt P, Demetri GD. Blay JY, et al. Lancet Oncol. 2015 May;16(5):550-60. doi: 10.1016/S1470-2045(15)70105-1. Epub 2015 Apr 14. Lancet Oncol. 2015. PMID: 25882987 Free PMC article. Clinical Trial.
- Imatinib: as adjuvant therapy for gastrointestinal stromal tumour.Sanford M, Scott LJ. Sanford M, et al. Drugs. 2010 Oct 22;70(15):1963-72. doi: 10.2165/11205000-000000000-00000. Drugs. 2010. PMID: 20883053 Review.
- [Indications for pre- and postoperative treatment with imatinib for gastrointestinal stromal tumors].Heger U, Weitz J, Lordick F. Heger U, et al. Chirurg. 2008 Jul;79(7):630-7. doi: 10.1007/s00104-008-1526-6. Chirurg. 2008. PMID: 18548219 Review. German.
- Nomogram for Predicting Recurrence-Free Survival of Primary Localized Gastrointestinal Stromal Tumor.Ran P, Tan T, Zhou H, Li J, Yang H, Li J, Zhang J. Ran P, et al. J Pers Med. 2023 Mar 10;13(3):498. doi: 10.3390/jpm13030498. J Pers Med. 2023. PMID: 36983680 Free PMC article.
- Development of Highly Sensitive Digital Droplet PCR for Detection of cKIT Mutations in Circulating Free DNA That Mediate Resistance to TKI Treatment for Gastrointestinal Stromal Tumor (GIST).Rassner M, Waldeck S, Follo M, Jilg S, Philipp U, Jolic M, Wehrle J, Jost PJ, Peschel C, Illert AL, Duyster J, Scherer F, von Bubnoff N. Rassner M, et al. Int J Mol Sci. 2023 Mar 12;24(6):5411. doi: 10.3390/ijms24065411. Int J Mol Sci. 2023. PMID: 36982486 Free PMC article.
- Plasma trough concentration of imatinib and its effect on therapeutic efficacy and adverse events in Japanese patients with GIST.Teranishi R, Takahashi T, Nishida T, Kurokawa Y, Nakajima K, Koh M, Nishigaki T, Saito T, Yamamoto K, Yamashita K, Tanaka K, Makino T, Motoori M, Omori T, Hirota S, Hayashi Y, Takehara T, Eguchi H, Doki Y. Teranishi R, et al. Int J Clin Oncol. 2023 Mar 27. doi: 10.1007/s10147-023-02325-x. Online ahead of print. Int J Clin Oncol. 2023. PMID: 36971916
- Unusual Acute, Massive Lower Gastrointestinal Bleeding Secondary to a Proximal Jejunal Gastrointestinal Stromal Tumor: A Case Report.Alsulaiman AA, AlAli MN, Essa MS, Alamri O, Albdah AM, Ahmad KS. Alsulaiman AA, et al. Cureus. 2023 Feb 22;15(2):e35287. doi: 10.7759/cureus.35287. eCollection 2023 Feb. Cureus. 2023. PMID: 36968934 Free PMC article.
- Neoadjuvant versus adjuvant imatinib in primary localized gastrointestinal stromal tumor.Ling J, Shi L, Cheng X, Fu Y, Lin Z, Zhao Y, Li Z, Zhang J, Hu H, Cai Y, Deng Y. Ling J, et al. J Gastrointest Oncol. 2023 Feb 28;14(1):73-84. doi: 10.21037/jgo-22-931. Epub 2023 Jan 10. J Gastrointest Oncol. 2023. PMID: 36915468 Free PMC article.
- Clinical Trial, Phase III
- Randomized Controlled Trial
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents / administration & dosage*
- Antineoplastic Agents / adverse effects
- Benzamides
- Chemotherapy, Adjuvant
- Double-Blind Method
- Female
- Gastrointestinal Stromal Tumors / mortality
- Gastrointestinal Stromal Tumors / pathology
- Gastrointestinal Stromal Tumors / surgery
- Gastrointestinal Stromal Tumors / therapy*
- Humans
- Imatinib Mesylate
- Male
- Middle Aged
- Piperazines / administration & dosage*
- Piperazines / adverse effects
- Pyrimidines / administration & dosage*
- Pyrimidines / adverse effects
- Antineoplastic Agents
- Benzamides
- Piperazines
- Pyrimidines
- Imatinib Mesylate
- ClinicalTrials.gov/NCT00041197
- Full Text Sources
- Other Literature Sources
- Medical
NCBI Literature Resources
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![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2915459/bin/nihms108869f3b.jpg)
Figure 3
Figure 3A. Recurrence-free survival for…
Figure 3
Figure 3A. Recurrence-free survival for tumor size ≥3 and
Figure 4
Overall survival.
Figure 4
Overall survival.
- Adjuvant imatinib in GIST: a self-fulfilling prophecy, or more?Hohenberger P. Hohenberger P. Lancet. 2009 Mar 28;373(9669):1058-60. doi: 10.1016/S0140-6736(09)60562-6. Epub 2009 Mar 18. Lancet. 2009. PMID: 19303138 No abstract available.
- One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial.Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt P. Joensuu H, et al. JAMA. 2012 Mar 28;307(12):1265-72. doi: 10.1001/jama.2012.347. JAMA. 2012. PMID: 22453568 Clinical Trial.
- Approval summary: imatinib mesylate in the adjuvant treatment of malignant gastrointestinal stromal tumors.Cohen MH, Cortazar P, Justice R, Pazdur R. Cohen MH, et al. Oncologist. 2010;15(3):300-7. doi: 10.1634/theoncologist.2009-0120. Epub 2010 Mar 3. Oncologist. 2010. PMID: 20200041 Free PMC article. Clinical Trial.
- Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial.Blay JY, Shen L, Kang YK, Rutkowski P, Qin S, Nosov D, Wan D, Trent J, Srimuninnimit V, Pápai Z, Le Cesne A, Novick S, Taningco L, Mo S, Green S, Reichardt P, Demetri GD. Blay JY, et al. Lancet Oncol. 2015 May;16(5):550-60. doi: 10.1016/S1470-2045(15)70105-1. Epub 2015 Apr 14. Lancet Oncol. 2015. PMID: 25882987 Free PMC article. Clinical Trial.
- Imatinib: as adjuvant therapy for gastrointestinal stromal tumour.Sanford M, Scott LJ. Sanford M, et al. Drugs. 2010 Oct 22;70(15):1963-72. doi: 10.2165/11205000-000000000-00000. Drugs. 2010. PMID: 20883053 Review.
- [Indications for pre- and postoperative treatment with imatinib for gastrointestinal stromal tumors].Heger U, Weitz J, Lordick F. Heger U, et al. Chirurg. 2008 Jul;79(7):630-7. doi: 10.1007/s00104-008-1526-6. Chirurg. 2008. PMID: 18548219 Review. German.
- Nomogram for Predicting Recurrence-Free Survival of Primary Localized Gastrointestinal Stromal Tumor.Ran P, Tan T, Zhou H, Li J, Yang H, Li J, Zhang J. Ran P, et al. J Pers Med. 2023 Mar 10;13(3):498. doi: 10.3390/jpm13030498. J Pers Med. 2023. PMID: 36983680 Free PMC article.
- Development of Highly Sensitive Digital Droplet PCR for Detection of cKIT Mutations in Circulating Free DNA That Mediate Resistance to TKI Treatment for Gastrointestinal Stromal Tumor (GIST).Rassner M, Waldeck S, Follo M, Jilg S, Philipp U, Jolic M, Wehrle J, Jost PJ, Peschel C, Illert AL, Duyster J, Scherer F, von Bubnoff N. Rassner M, et al. Int J Mol Sci. 2023 Mar 12;24(6):5411. doi: 10.3390/ijms24065411. Int J Mol Sci. 2023. PMID: 36982486 Free PMC article.
- Plasma trough concentration of imatinib and its effect on therapeutic efficacy and adverse events in Japanese patients with GIST.Teranishi R, Takahashi T, Nishida T, Kurokawa Y, Nakajima K, Koh M, Nishigaki T, Saito T, Yamamoto K, Yamashita K, Tanaka K, Makino T, Motoori M, Omori T, Hirota S, Hayashi Y, Takehara T, Eguchi H, Doki Y. Teranishi R, et al. Int J Clin Oncol. 2023 Mar 27. doi: 10.1007/s10147-023-02325-x. Online ahead of print. Int J Clin Oncol. 2023. PMID: 36971916
- Unusual Acute, Massive Lower Gastrointestinal Bleeding Secondary to a Proximal Jejunal Gastrointestinal Stromal Tumor: A Case Report.Alsulaiman AA, AlAli MN, Essa MS, Alamri O, Albdah AM, Ahmad KS. Alsulaiman AA, et al. Cureus. 2023 Feb 22;15(2):e35287. doi: 10.7759/cureus.35287. eCollection 2023 Feb. Cureus. 2023. PMID: 36968934 Free PMC article.
- Neoadjuvant versus adjuvant imatinib in primary localized gastrointestinal stromal tumor.Ling J, Shi L, Cheng X, Fu Y, Lin Z, Zhao Y, Li Z, Zhang J, Hu H, Cai Y, Deng Y. Ling J, et al. J Gastrointest Oncol. 2023 Feb 28;14(1):73-84. doi: 10.21037/jgo-22-931. Epub 2023 Jan 10. J Gastrointest Oncol. 2023. PMID: 36915468 Free PMC article.
- Clinical Trial, Phase III
- Randomized Controlled Trial
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents / administration & dosage*
- Antineoplastic Agents / adverse effects
- Benzamides
- Chemotherapy, Adjuvant
- Double-Blind Method
- Female
- Gastrointestinal Stromal Tumors / mortality
- Gastrointestinal Stromal Tumors / pathology
- Gastrointestinal Stromal Tumors / surgery
- Gastrointestinal Stromal Tumors / therapy*
- Humans
- Imatinib Mesylate
- Male
- Middle Aged
- Piperazines / administration & dosage*
- Piperazines / adverse effects
- Pyrimidines / administration & dosage*
- Pyrimidines / adverse effects
- Antineoplastic Agents
- Benzamides
- Piperazines
- Pyrimidines
- Imatinib Mesylate
- ClinicalTrials.gov/NCT00041197
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2915459/bin/nihms108869f3c.jpg)
Figure 4
Overall survival.
Figure 4
Overall survival.
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2915459/bin/nihms108869f4.jpg)
Source: PubMed