Studies differ over 400 mg. vs. 800 mg.
By Richard Palmer
Do you need an 800-pound Gleevec gorilla in your corner or will a 400- pound one thrash GIST just as well?
Well, for the moment, the answer depends on which side of the Atlantic you happen to be sitting.
European researchers and U.S. researchers both gave presentations at the annual meeting of the American Society of Clinical Oncology held May 31-June 3 in Chicago. Both presentations were on the phase III study of Gleevec for GIST, where patients were given daily doses of either 400 mg. or 800 mg. of Gleevec. One key question researchers aimed to answer is whether a high dose of Gleevec is better for patients’ survival.
With many of the 25,000 cancer professionals in attendance, the U.S. group took the podium the afternoon of Saturday, May 31. With results from 746 patients from 57 institutions, the study’s authors said they’d found “no significant differences to date (median: 14 months on Gleevec) between the two dose levels.”
Fifteen minutes later, the European
group took the podium and presented
their findings from 946 patients at 56
centers in 13 countries. They estimated
that “progression-free survival was
significantly better” at 800 mg. per
day. How much better? The group
calculated that 58 percent of patients
on 800 mg. would be progression-free as
of a 17-month median, compared to 50
percent of patients on 400 mg. — a
difference of 8 percent.
Two studies, opposing conclusions. What’s a GIST patient to do?
For starters, both studies were interim and that means the conclusions are subject to change. Indeed, the abstract of the European study originally submitted to ASCO weeks in advance of the convention largely agreed with the U.S. group’s findings, saying the “small observed advantage of the high dose arm is not statistically significant.” But abstracts often contain “immature data,” researchers say, which can and do change over time.
The Europeans had an opportunity to gather more up-to-date results shortly before ASCO convened, did an actuarial estimate on the findings, and presented updated results. This illustrates that a difference of a couple of months can change the outcome of a study.
Another factor may come into play, and it involves the way the clinical trials are set up. In these studies, half the patients were started on 400 mg./ day, half on 800 mg./day. If a patient’s dose is lowered due to severe side effects, or increased due to disease progression, it doesn’t matter to the researchers — patients are still counted as if they stayed on their starting dose. This is called “intent to treat” in clinical trial lingo.
While “intent to treat” is a statistically proven way of summarizing the results of a trial, it may not reflect reality.
In an informal survey of Life Raft Group members, nearly half of those who started on 800 mg. Gleevec had to reduce their dose. Some were only on 800 mg. for a few weeks before side effects forced them to drop to 400 mg. Yet for trial purposes, they are counted as if they’re still on 800 mg.
So the European study’s preliminary findings that 800 mg. is “significantly better” than 400 mg. may be, if anything, an understatement.
If many of those patients reported as being 800 mg. are, as the Life Raft Group’s experience shows, really on 400 mg., the effectiveness of 800 mg. is being discounted.
While U.S. researchers say their data so far is inconclusive, the media department of M.D. Anderson Cancer Center in Houston, Texas, wasted no time in jumping to a conclusion: Two days after the ASCO presentation, a press release was put out by MDA, titled “Doubling Dose of Gleevec to Treat GIST is Not Any More Beneficial,” beginning with this statement: “Less is perhaps more when it comes to using Gleevec to treat advanced gastrointestinal stromal tumors (GIST) …”
If the European findings are any indication, oncologists treating GIST patients with Gleevec may want to hold off discounting an increase in dose for patients who experience disease progression.
Also of interest
Gleevec may be the “magic cancer bullet” but it’s far from a cure. Of the 946 patients in the European study, 322 experienced disease progression as of the 17-month median, and 185 had died. Of the 746 patients on the U.S. study, 260 were off the trial at the 14- month median, and 190 had died. Nonetheless, the U.S. study did confirm the “extraordinary anti-tumor activity (of Gleevec) in patients with metastatic GIST.”
