Stopping Gleevec
The question of whether or not a patient can stop Gleevec comes up frequently. The answer is highly dependent on the treatment stage that the patient is in.
Neoadjuvant
Gleevec is generally continued until just prior to surgery to remove the primary tumor. It may or may not be restarted after surgery (adjuvant Gleevec).
Adjuvant
In the clinical trial that resulted in adjuvant Gleevec approval in the United States, Gleevec was given for one year and then stopped. However, the FDA approval for adjuvant Gleevec does not specify a treatment duration. The treatment duration is up to the doctor (with patient input). The doctor might consider factors such as risk of recurrence, mutational status (does the patient have a Gleevec-responsive mutation), new trial data and how well the patient is tolerating Gleevec when determining a treatment duration.
Metastatic Disease still responding to Gleevec
For metastatic GIST that is still responding to Gleevec, the standard treatment would be to continue Gleevec as long as possible. Stopping the Gleevec would probably be considered “investigational” and should probably be reserved for a clinical trial setting. In fact, there is a long-running trial that has investigated that very thing, the French BFR14 trial.
One of the conclusions published about this trial was:
“Imatinib interruption results in rapid progression in most patients with advanced GIST, and cannot be recommended in routine practice unless patient experience significant toxicity.” (http://jco.ascopubs.org/cgi/content/full/25/9/1107)
At the 2003 Helsinki and Barcelona conference on the Clinical Managment of GIST (before the approval of Sutent for Gleevec-resistant GIST), "Dr. Demetri postulated that signal transduction inhibition with imatinib may result in cell suppression or dormancy but not cell death in some sensitive clones. In essence, these cells “wake up” when the drug is discontinued. Post-imatinib recurrences of GIST have been found to be highly aggressive, placing the patient at risk for marked acceleration of tumor growth and a rapidly fatal course. Therefore, it is advisable not to terminate imatinib therapy as long as the patient is tolerating the drug, especially if there is evidence that only limited progressive disease is present (e.g., 1 focal resistant clone that might be managed by a locoregional measure such as surgical resection or radiofrequency ablation). Chances are good that imatinib will continue to shrink or stabilize most sites of disease for a considerable duration even in a patient who has developed a limited focus of clonal resistance to imatinib."
The approval of Sutent gives patients another option, but the important point to remember is that some type of kinase inhibition should be maintained in GIST patients as long as they are able to tolerate it.
See Imatinib Discontinuation can result in "PET Flare" for the full story.
Also see:
From the NCI: Imatinib “Treatment Holiday” risks disease progression (http://www.cancer.gov/clinicaltrials/results/GIST0407)
From the LRG clinical trials database; see the “Trial Results” links for the BFR14 trial near the bottom of this page: http://gisttrials.fmgateway.com/iLRG/details.php?Trial=50
From the JNCCN guidelines (NCCN Task Force Report: Optimal Management of Patients with Gastrointestinal Stromal Tumor (GIST)—Update of the NCCN Clinical Practice Guidelines)1:
"The therapeutic effect (of imatinib) should be monitored using positron emission tomography (PET) or CT. Patients should remain on imatinib or sunitinib as long as possible; however, if the patient is no longer receiving clinical benefit from imatinib or sunitinib, then the drugs should be discontinued and best supportive care used."
Metastatic Disease resistant to Gleevec
For Gleevec-resistant GIST, the JNCCN guidelines recommend continuing Gleevec or Sutent1:
“When patients have experienced progression on imatinib
and sunitinib and are not candidates for a clinical
trial, the task force believes that discontinuing
therapy targeting KIT/PDGFRA may lead to accelerated tumor growth by withdrawing control of sensitive clones of the disease (even if limited sites of
disease have been shown to exhibit resistance to therapy
and hence to progress more rapidly). Therefore,
absent a clinical trial testing a different hypothesis,
the task force recommended that patients with limited
progression of GIST should continue imatinib
or sunitinib at a dose they can tolerate.”
Also see: Managing Progression: Charles D. Blanke, MD discusses Gleevec Resistance
Localized progression
Localized progression is the progression of one or a few (but not all) tumors while on Gleevec. The progressing tumor(s) are treated by surgery, radiofrequency ablation (RFA) or embolization if possible. Gleevec is typically continued at the same dose or an increased dose as tolerated. A change to Sutent can be considered, however continuation of some type of kinase inhibitor is recommended2.
Widespread progression
Gleevec is typically continued at an increased dose (800 mg if tolerated) or a change to Sutent can be considered2.
Stopping Gleevec and other drugs before Surgery
Gleevec can be given to patients until surgery and can be restarted when the patients can start oral intake1.
According to the JNCCN guidelines, Sutent should be stopped 5 to 7 days before surgery and is usually restarted 2 weeks after surgery1. A small retrospective analysis of 30 GIST patients undergoing surgery at Dana-Farber Cancer Center concluded that there were no differences in wound-healing complications following surgery between patients on Gleevec or Sutent3. Given the small sample size and the retrospective nature of the analysis, further studies will be required to confirm these results. According to this 2007 ASCO abstract and presentation, the practice at that time was to continue sunitinib until 1-2 days prior to surgery and resume as soon as possible after hospital discharge, which usually coincided with the patient's first postoperative visit.
References
2. NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma, V.2.2008 http://www.nccn.org/ (registration required to view the guidelines)
3. Perioperative sunitinib dosing around extensive resections of imatinib-resistant metastatic gastrointestinal stromal tumors.
C. P. Raut, J. A. Morgan, M. T. Quigley, S. George, A. J. Wagner, G. D. Demetri, M. M. Bertagnolli
