/Adjuvant Imatinib Study Updates Results

Adjuvant Imatinib Study Updates Results

By |2018-10-30T13:56:09+00:00December 16th, 2015|Gleevec, News, Newsletter, Research, Survival Strategies|

A recent study further documented the advantage of three years of adjuvant imatinib versus one year in high-risk GIST patients. The study, which is to be published in the Journal of Clinical Oncology, was authored by a number of the leading European researchers in GIST, including Heikki Joensuu of Finland, Kirsten Sundby Hall of Norway, Peter Reichardt and Peter Hohenberger of Germany, and Sebastian Bauer, a member of the LRG Research Team, also from Germany, among others.

The article was a follow-up to the original study that reported a significant benefit in overall survival for three years of adjuvant treatment with 400mg imatinib versus one year (see www.liferaftgroup.org/2011/08/adjuvant-gleevec-star-of-asco/ for details) and ultimately led to the FDA approving three years of adjuvant imatinib for advanced GIST patients.

The initial study included 400 patients with categorized by high-risk (either one of the following):

Largest tumor diameter is over 10cm

Mitosis count is over 10/50 high power microscopic fields (HPF)

Largest tumor diameter over 5cm the mitosis count is over 5/50 HPF) KIT-positive GIST that had successful surgery between 2004 and 2008. After surgery, patients were randomly assigned to one of two arms, and received either one year or three years of imatinib.

The follow up study, “Short (12 months) versus long (36 months) duration of adjuvant treatment with the tyrosine kinase inhibitor imatinib mesylate of operable GIST with a high risk for recurrence,” had the same protocol as the original study. 280 patients were reassessed to see if the survival benefit demonstrated in the previous study, persisted. It did – patients had a five-year recurrence-free survival rate of 52.3% in the one-year group vs. 71.1% in the three-year group, and an overall survival rate of 85.3% in the one- year group vs. 91.9% in the three- year group. Both of these comparisons proved to be statistically significant (p<.001 and p=.036 respectively).

While confirmation of the benefits of three years of adjuvant imatinib is an important finding, a few other questions persist that may warrant further investigation. I asked the primary author of the study, Dr. Heikki Joensuu to respond to these questions.

First, this study looked exclusively at high-risk patients. What do those findings mean to those patients in an intermediate risk category?  Dr. Joensuu responded by stating, “The trial was carried out in the high-risk patient population, and the results cannot be applied to lower risk GISTs. In fact, the subgroup analyses, though limited in power, suggest that patients with GIST with a high mitotic count are the ones who benefit from three-year adjuvant imatinib, whereas the patents with a low mitotic count do not.”

Dr. Joensuu adds, “The concept of ‘intermediate risk GIST’ is poorly defined. The malignancy potential of GISTs varies from virtually benign tumors to highly malignant cancers, and it is difficult to define accurately any intermediate groups in this continuum. In practice, the criteria used in the SSGXVII/AIO trial work reasonably well in patient selection for adjuvant treatment, and the prognostic heat maps may also be helpful.”  The SSGXVIII/AIO (The Scandinavian Sarcoma Group XVII/Arbeitgemeinschaft Internistische Onkologie) trial assessed patients with resected high-risk tumors, as well as those with single metastases who received complete resection of the primary tumor and the metastases. Prognostic heat maps are contour maps that assess the risk of each tumor in which the color red means a high risk, and blue means a low risk.(see www.liferaftgroup.org/risk-of-recurrence-details/ for further details about heat maps).

Second, a number of patients have reached the three-year mark of imatinib treatment and are stable or NED, and are wondering whether to continue on the medication. When Dr. Joensuu was asked what his opinion was on patients continuing treatment for patients beyond the three-year mark, he responded, “The patient needs to have NED – being stable might indicate that overt metastases have been detected, which entails permanent tyrosine kinase inhibitor (TKI) therapy. Some patients who are estimated to have a high risk for GIST recurrence despite macroscopically complete surgery might benefit from adjuvant imatinib administered for longer than three years. This remains, however, a hypothesis with little evidence to support it. There may also be patients who are harmed by long treatments, such as patients who are estimated to have a high risk but who were cured by surgery. Therefore, two randomized trials that compare longer than three years of adjuvant imatinib with the standard (i.e three years of imatinib) have been launched in Europe and are accruing patients.“

Dr. Joensuu concludes, “At present, the standard duration of adjuvant imatinib is three years; longer treatments than this have unproven benefit. It is likely very important to perform imaging of the abdomen and pelvis frequently after adjuvant imatinib has been discontinued to detect recurrence early should it arise. Recurrent GIST usually responds well to re-starting of imatinib, and the risk of emergence of drug resistance is likely lower the smaller the tumor bulk. The ongoing trials testing the longer regimens are highly important to inform us about the optimal way to treat patients who have undergone surgery for high-risk GIST.”

Data from the LRG patient registry reveals high-risk patients who have progressed after stopping imatinib even beyond the three-year mark. While this is a complicated question with a number of variables from patient to patient, a study looking at patients taking imatinib for longer time periods and assessing the benefit would be very useful, in that it would help patients make a more informed decision about whether to continue treatment.  We will eagerly watch as the European studies Dr. Joensuu mentions progress and report results. Until that time, the LRG maintains that consulting with a GIST specialist who is familiar with your individual risk factors and keeping apprised of the latest medical research is the best way to make an informed decision before stopping Gleevec.     

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