June 6, 2011 (Chicago, Illinois) — Extended adjuvant treatment with imatinib (Gleevec) improves survival in patients with high-risk gastrointestinal stromal tumors (GIST). Imatinib administered for 3 years improved both relapse-free survival and overall survival in patients after surgery, compared with 1 year of adjuvant treatment.
"The clinical behavior of GIST is variable," said lead author Heikki Joensuu, MD, professor of oncology at Helsinki University Central Hospital in Finland. "But high-risk GIST has a 50% risk of recurrence 5 years after surgery. There is a strong rationale for studying imatinib as an adjuvant therapy, and it is effective in the treatment of advanced GIST."
Previous data have shown that initiating adjuvant imatinib therapy reduces the risk for GIST recurrence, compared with placebo. "But the effect of imatinib on overall survival is not known," said Dr. Joensuu, who presented the findings during the plenary session here at the American Society of Clinical Oncology 2011 Annual Meeting.
In the study by Dr. Joensuu and colleagues, however, longer treatment prevented recurrence, and that was statistically significant.
The 5-year relapse-free survival in patients was higher in those who received 3 years of treatment than in those who received 1 year (65.6% vs 47.9%; hazard ratio [HR], 0.46; P < .0001). The 5-year overall survival was also better in patients who received 3 years of therapy (92.0% vs 81.7%; HR. 0.45; P = .019).
"We are looking at 92% in the 3-year group, and that is very high," said Dr. Joensuu. "We are making substantial improvement here. Those assigned to the 3-year group are doing better than those assigned to 1 year of therapy. There were 55% fewer deaths in that group."
Results Are Compelling
Adjuvant imatinib administered for 1 year after surgery has been shown to improve the rate of recurrence-free survival in patients diagnosed with operable GIST.
The authors randomized 400 patients (200 in each group) with histologically diagnosed KIT-positive GIST, and risk for recurrence was estimated using the modified consensus criteria. The patients were enrolled from 24 centers, from February 2004 to September 2009, and baseline characteristics were balanced between the 2 groups. The most common tumor site was the stomach, and approximately 20% of patients had tumor rupture.
Patients received imatinib 400 mg/day for either 1 year or 3 years.
The primary objective was recurrence-free survival; secondary objectives included survival and treatment safety. The median time to follow-up was 54 months.
Imatinib was generally well tolerated, and most adverse events were mild in severity. The most frequently observed events were anemia, fatigue, nausea, diarrhea, and muscle cramps. However, 7.7% of the patients in the 1-year group and 13.7% who received 3 months of therapy halted treatment because of adverse events.
Most patients in the high-risk population currently receive imatinib for 1 year, explained Dr. Joensuu, but "these results are very compelling."
"It is possible to give it for a longer period of time," he said, "and some patients might benefit from a longer period, but there are no data to support that."
There are no randomized trials to support extending treatment beyond 3 years, he emphasized. Studies evaluating GIST risk factors that will address longer treatment times with adjuvant imatinib — including a single-group nonrandomized study examining 5-year adjuvant treatment — are currently underway.
Dr. Joensuu pointed out that there is evidence that when imatinib is restarted after a recurrence, patients will usually respond. In this study, imatinib resistance was not a problem.
But for How Long?
The authors of this study conclude that longer-term imatinib improved recurrence-free survival and overall survival, noted Charles D. Blanke, MD, from the University of British Columbia, Vancouver, Canada. "The goals were reasonable and the methodologies for primary and secondary objectives were sound."
That said, the study does raise a number of issues, explained Dr. Blanke, who served as the discussant for the study.
One question that remains unanswered is the ideal duration of postoperative therapy. It is also unclear if the 3-year therapy just delays disease recurrence, without curing the disease, he pointed out.
"As of today, we still don't know how long to administer postoperative imatinib in GIST," he said. "To derive the best interval, we still have to test a number of different durations. Of course, economic issues and the number of patients available for clinical trials limit the feasibility of doing so."
In fact, he added, the National Cancer Institute rejected the 5- to 10-year vs lifetime imatinib trial that was recently proposed, and "I doubt that they will change their mind," even after the results of this study.
These results clearly demonstrated that 3 years of imatinib are better than 1 for recurrence-free survival and, to date, overall survival. "If you have a patient with a high risk — at least defined by the study — GIST, giving him or her 3 years of imatinib represents the new gold standard," he said.
"For now, with the overall survival benefit demonstrated with immediate postoperative imatinib, it is no longer acceptable to withhold treatment in the adjuvant setting, hoping to 'catch up' when the patient has recurrent metastatic disease," Dr. Blanke said.
"But should we treat longer than 3 years?" he asked. "Should we treat forever?"
I personally will offer patients treatments to eternity.
There are plenty of reasons to think that giving imatinib for a longer period would be better, but that theory remains unproven," he continued. "For now, if I was a patient with high-risk GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatments to eternity — meaning indefinitely."
Dr. Blanke added that he does "reserve the right to change his mind," pending longer-term results.
The study was funded by Novartis, and also received academic funding. Dr. Joensuu reports serving as a consultant/advisor for and receiving honoraria from Novartis. Several coauthors report financial relationships with Novartis, the manufacturer of imatinib, as noted in the abstract.
American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting. Abstract LBA1. Presented June 5, 2011.
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