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Long-term Results of Adjuvant Imatinib Mesylate in Localized, High-Risk, Primary Gastrointestinal Stromal Tumor: ACOSOG Z9000 (Alliance) Intergroup Phase 2 Trial

DeMatteo, Ronald P. MD*; Ballman, Karla V. PhD; Antonescu, Cristina R. MD*; Corless, Christopher MD; Kolesnikova, Violetta MD; von Mehren, Margaret MD§; McCarter, Martin D. MD; Norton, Jeffrey MD; Maki, Robert G. MD, PhD**; Pisters, Peter W. T. MD††; Demetri, George D. MD‡‡; Brennan, Murray F. MD*; Owzar, Kouros PhD§§;

doi: 10.1097/SLA.0b013e3182a15eb7
Papers of the 133rd ASA Annual Meeting

Objective: To conduct the first adjuvant trial of imatinib mesylate for treatment of gastrointestinal stromal tumor (GIST).

Background: GIST is the most common sarcoma. Although surgical resection has been the mainstay of therapy for localized, primary GIST, postoperative tumor recurrence is common. The KIT protooncogene or, less frequently, platelet-derived growth factor receptor alpha is mutated in GIST; the gene products of both are inhibited by imatinib mesylate.

Methods: This was a phase II, intergroup trial led by the American College of Surgeons Oncology Group, registered at as NCT00025246. From September 2001 to September 2003, we accrued 106 patients who had undergone complete gross tumor removal but were deemed at high risk for recurrence. Patients were prescribed imatinib 400 mg per day for 1 year and followed with serial radiologic evaluation. The primary endpoint was overall survival (OS).

Results: After a median follow-up of 7.7 years, the 1-, 3-, and 5-year OS rates were 99%, 97%, and 83%, which compared favorably with a historical 5-year OS rate of 35%. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 96%, 60%, and 40%. On univariable analysis, age and mitotic rate were associated with OS. On multivariable analysis, the RFS rate was lower with increasing tumor size, small bowel site, KIT exon 9 mutation, high mitotic rate, and older age.

Conclusions: Adjuvant imatinib in patients with primary GIST who are at high risk of recurrence prolongs OS compared with that of historical controls. Optimal duration of adjuvant therapy remains undefined. (NCT00025246)

Gastrointestinal stromal tumor is the most common sarcoma. We show that postoperative use of the small molecule inhibitor imatinib improves survival. Outcome depended on pathologic and molecular features of the tumor.

*Memorial Sloan–Kettering Cancer Center, New York, NY

Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN

Oregon Health Sciences University, Portland, OR

§Fox Chase Cancer Center, Philadelphia, PA

University of Colorado School of Medicine, Aurora, CO

Stanford University School of Medicine, Stanford CA

**Mt Sinai School of Medicine, New York, NY

††University of Texas MD Anderson Cancer Center, Houston, TX

‡‡Dana Farber Cancer Institute, Boston, MA; and

§§Alliance Statistics and Data Center, Duke University, Durham, NC

Correspondence: Ronald P. DeMatteo, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; E-mail:

Disclosure: This work was supported by grants U10 CA076001 (ACOSOG) and CA94503 and CA102613 (R.P.D.) from the National Cancer Institute. The research for ACOSOG Z9000 (Alliance) was also supported, in part, by grants from the National Cancer Institute (CA31946) to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli, MD, Chair) and to the Alliance Statistics and Data Center (Daniel J. Sargent, PhD, CA33601). Dr DeMatteo was the recipient of a Clinical Investigator Award from the Society of Surgical Oncology. ACOSOG Z9000 was conducted through a contract between Novartis and National Cancer Institute under CRADA 1111.1. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Drs DeMatteo, Corless, von Mehren Maki, Pisters, and Demetri report receiving honoraria from Novartis and have served on Novartis advisory boards. No other relevant conflicts of interest were reported.

© 2013 by Lippincott Williams & Wilkins.