Note: On December, 19th, 2008, the FDA approved adjuvant Gleevec in the United States. In the FDA press release, they noted that the optimal treatment duration is not known. This article (Questions to consider for adjuvant treatment)was written in December, 2007 and is being updated to reflect the recent FDA approval.
GIST patients face many decisions about their treatment. Many GIST patients have surgery to remove a primary tumor and do not have detectable metastases at the time of surgery. This large group of patients faces the decision of whether or not to take Gleevec to try to prevent or delay a recurrence. Adjuvant therapy refers to additional treatment given after a main mode of therapy (the main treatment is usually surgery). For example, Gleevec given after surgery in hopes of preventing or delaying a recurrence is called adjuvant therapy.
Some limitations of adjuvant trials:
- It will be some time before results are final.
- Patients may continue to take Gleevec on their own after the trial period. This may affect the trial results.
- The trials only examine lower doses of Gleevec.
- All of the existing adjuvant Gleevec trials give Gleevec (or placebo) for a fixed period of time (varying from one to three years) and then Gleevec is discontinued.
Does adjuvant Gleevec prevent recurrence?
This is unknown and the subject of the trials. The Z9001 trial was stopped early because it did show that, at a minimum, Gleevec at least dramatically delayed resistance (see Clinical trial confirms Gleevec reduces recurrence). It is well established that patients with measurable disease that stop taking Gleevec have a very high chance of progression. Gleevec does not kill all GIST tumor cells. Some residual cells remain alive after/during Gleevec treatment which become active again after Gleevec is stopped. The number of residual cells may vary greatly from patient to patient. Some may only have a small number of viable cells left and, for others, the vast majority may still be viable.
Does adjuvant Gleevec promote resistance?
This is unknown. For KIT exon 9 patients, the 400 mg dose being used in adjuvant treatment has been shown to be ineffective as a first-line treatment against measurable disease. For patients with measurable disease, Heinrich et al. showed that patients on high-dose Gleevec respond 8 times as often as patients on low-dose Gleevec. Debiec-Rychter et al. demonstrated that exon 9 patients on high-dose have a median progression-free survival time that is almost 5 times as long as patients on low-dose Gleevec.
In the lab, one of the ways scientists use to produce Gleevec-resistant cell lines (such as the CML cell line, K562/G01) is to culture the cell line in a sub-optimal concentration of Gleevec for several months. Thus, one wonders if giving an exon 9 patient 400 mg of Gleevec when there is no visible tumor to gauge Gleevec effectiveness could lead to premature resistance.
Not all GIST patients are at high risk of recurrence. Patients at low risk of recurrence may never have a recurrence or they may have a recurrence 10 or more years from now. By that time, it is likely that we will understand GIST much better and have even better drugs that we do today. Adjuvant Gleevec makes much more sense for patients with a high risk of recurrence. The ongoing adjuvant trials are for patients with high and intermediate risk.
Can we predict adjuvant Gleevec benefit?
No, but in the absence of clinical trial data, we can generate some hypotheses from what we already know:
Most likely to benefit:
- High-risk patients with:
– Exon 11 mutations
– Exon 9 patients taking high-dose Gleevec on an adjuvant basis
Least likely to benefit:
- Low-risk patients
- High-risk patients with:
– Exon 9 mutations while taking low-dose Gleevec on an adjuvant basis
– Non-responsive mutations
- PDGFRA D842A, etc
- Wild-type GIST (Note: This is more speculative than others.)
Note: Sutent has also shown good activity for exon 9 mutations in second-line therapy; however, no adjuvant trials have tested Sutent for GIST.
Recommended or not, many patients are taking adjuvant Gleevec outside of clinical trials. By understanding some of the issues regarding adjuvant Gleevec, patients and their doctors can make more informed choices about adjuvant Gleevec.