Life Raft raises research questions

By Norman J. Scherzer Executive Director, Life Raft Group

The different results of the European and American studies on whether progression is linked to dosage level will likely generate an attempt by the two groups to reconcile their findings. The Americans found that progression was not related to dosage level; the Europeans found that it was. Both groups used intent to treat (starting dosage) as their statistical model. Neither looked at the actual dosage delivered (changed dosage).

Given their conflicting results, the researchers will likely investigate whether they had a somewhat different distribution of molecular mutations or a different percentage of patients with changes in dosage. Unfortunately, that will miss the point that we need to look at the actual dosage delivered in addition to the initial dosage (intent to treat).

We recognize that intent to treat is the statistical gold standard of cancer research protocols. But, GIST patients want to know what dose will keep them from relapsing. It is disturbing that even though the Gleevec trials started nearly three years ago, we are aware of no group of medical researchers that have analyzed the actual dose patients were taking when they relapsed.

It is just hard to understand why, for example, a patient with an initial starting dosage of 800 mg. a day who is switched to 400 mg. a day after two weeks and then relapses after two years would be counted by both the American and European group as if he/ she was still on 800 mg. per day. Given the fact that the Life Raft Group has found that about 50 percent of GIST patients have a change in dosage — and that one could speculate that these changes were disproportionately due to higher dosage levels having to be lowered because of side effects — the current inattention to actual dosage seems shortsighted. More important, it is potentially dangerous to those GIST patients struggling to survive the lethal time gaps of research protocols.

The fact that there is yet no consistent procedure to measure the actual drug concentration level of Gleevec in GIST patients over time further compounds this situation. Imagine that the patient in the example above began at 800 mg. per day, decreased to 400 mg. per day and, when evaluated, only had a drug concentration level equivalent to 300 mg. per day.

This editorial comment represents the personal views of this reporter and is not intended to be confrontational nor disrespectful of the many competent and caring physicians involved in this research. The team of LRG members who contributed to this editorial was concerned that we might alienate the very physicians we depend upon for the care of GIST patients. Although our points are sometimes strong our confidence in the ability of the physician community to handle constructive criticism is even stronger.

It is time, however, for a wake-up call. If it is possible that higher actual dosages can prevent relapses we must move quickly to evaluate that by looking at actual dosage delivered. At the same time we should evaluate drug concentration levels.

In the interim, if one takes the perspective of good preventive care it seems reasonable that if a higher dosage turns out to prevent relapse it would be much more useful to be at that higher dose rather than take a lower dose until relapse occurs, and then hope that the higher dose can catch up with progressing disease.

Learning Experience

ASCO proved to be a valuable learning experience for the Life Raft Group. We have learned that abstracts may be preliminary and may be superceded by more current data at the actual meeting. We have learned that things are not always as they appear, not even “scientific data.” We have learned that it is extremely valuable to have direct access to individual researchers to glean information and observations that are not part of a formal paper. We have learned that the research community is made up of distinct parts and interests and that they function within a set of rules and guidelines that do not always produce the maximum level of coordination. We have learned that the perspective of patients is not always the same as that of the research community, regardless of the best of intentions and skills.

We recognize that we do not have all the answers and that those we provide are subject to human error. Accordingly we invite those with points of view different from those expressed in this editorial to contribute them to future newsletter editions.