Post-Surgery Preventive Imatinib (Adjuvant Gleevec)

On December 19, 2008 the US FDA announced approval of the use of imatinib (Gleevec) as adjuvant treatment (prescribed after complete surgical resection) to prevent recurrence of primary GIST.  LINK HERE to the brief announcement.  Subsequently the European Union and many other countries have also approved this use.

On January 31, 2012 the FDA issued a news release approving longer adjuvant use of imatinib (Gleevec) based on a trial showing an extended duration of progression-free survival or patients who took imatinib for 3 yeas post-surgery compared to those who took it for one year post-surgery.

Adjuvant imatinib (Gleevec) means taking the drug after complete resection of a primary gastrointestinal stromal tumor (GIST).   Trials are underway to determine whether administering imatinib (Gleevec) for some period of time (1, 2, 3, or 5 years) after complete resection of a primary tumor will reduce the percentage of patients who develop recurrences or metastases of GIST.   (Note that once GIST has developed metastases, then even if all visible disease has been surgically removed, Gleevec is approved by the FDA and this is not considered adjuvant treatment.)

Data are fairly clear that, after complete resection of a primary tumor, patients in the very-low and low-risk groups do not need adjuvant Gleevec.  The question is whether patients with intermediate-risk or high-risk GISTs will benefit.

For two experts’ comments about adjuvant imatinib, link to a Q&A piece by Dr. Blay and Dr. Trent on our page Adjuvant Imatinib Opinions.

Dr. DeMatteo’s original presentation at ASCO showed the data shown in the following table for recurrence-free survival at the 1-year mark for subjects grouped by the size of their resected primary tumors.

Recurrence-free survival at the 1-year mark Tumor size
3-6 cm 6-10 cm  > 10 cm
imatinib group 100% 96% 96%
placebo group 95% 80% 67%
significant difference? no p<.01 p<.001

In his ASCO presentation Dr. DeMatteo commented that after the 1-year period of taking either imatinib or placebo ended, the curves for recurrence-free survival in the imatinib arm appeared to change slope, beginning to show increased rates of recurrence by about 18 months (6 months after the year of imatinib ended).  However, this potential trend was analyzed later and reported on in the following paper:

Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance)

In conclusion the paper states:  Adjuvant imatinib in patients with primary GIST who are at high risk of recurrence prolongs Overall Survival compared with that of historical controls.  Optimal duration of adjuvant therapy remains undefined.

RTOG 0132 Initial Analysis

A preliminary analysis of this trial has been published as follows:

Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M.
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 Jan 1;99(1):42-7. PubMed PMID: 18942073; PubMed Central PMCID:PMC2606912.
This paper will be free-access in PubMed central in January 2010.

This trial selected patients with large and difficult-to-resect primary tumors (Group A, N=30) plus another group of patients with recurrent or metastatic GIST that could be resected (Group B, N=22).  Patients took imatinib for 8-12 weeks pre-surgery, then for 2 years post-surgery.  This is considered adjuvant therapy ONLY for Group A.  Progression-free survival for Group A was 82.7% at the end of the 2-year period of adjuvant imatinib, and the estimated progression-free survival ater one year off the drug (the 3-year mark post-surgery) was 68%.

2008 Analysis Updates and Critiques

At the 2008 ASCO meeting there was a special educational session with summary presentations by Drs. Demetri, DeMatteo, and Blay.  The latter two of these presentations are relevant to adjuvant imatinib therapy.  The session link is:  Gastrointestinal Stromal Tumor (GIST) Comes of Age: Current Management

Once you have linked to the page above, choose Dr. DeMatteo’s presentation  “Surgical management of GIST including imatinib-refractory disease” (the second one shown) and click either the icon for video or the icon for audio at the right the screen.

Likewise, for Dr. Blay’s presentation “Controversy in the adjuvant treatment of GIST,”  link to the page above and then choose the desired icon (video or slides) for the third presentation shown.

Medscape also offers access to an analysis written by Peter Hohenberger, MD entitled “Should Adjuvant Imatinib Be Used as Primary Treatment for Gastrointestinal Stromal Tumors?”  This discussion paper was originally published in the journal Nature Clinical Practice: Oncology.  Access to Medscape is free after a registration.  To link to the Medscape online reprint, click the title above.