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There were 800 patients who received either chemotherapy or immunochemotherapy. This is therefore a very large trial and it was sufficiently powered to detect a difference in median progression-free survival of 14 months at between 3 and 5 years follow-up, that is when a total of 357 progressions had occurred. An interim analysis was planned for when two thirds this number of events had occurred (ie 238 events) against the possibility that FCR was even better than FC than expected. It would obviously be unethical to continue a trial if one arm was proving to be so much better than the other arm.
The primary end point was chosen to be progression-free survival (pfs) defined as the time between randomization and the date of first documented disease progression or death. The reason for this is that in hematological diseases generally, pfs has been shown to correlate with overall survival and for the benefit of patients we want trials to be as short as possible. I have tended to argue against this decision because in CLL this has not been the case. We have seen trials suggesting that F gives a longer pfs than chlorambucil and that FC gives a better pfs than both. However, patients who fail the lesser regimen can later switch to the better regimen and hitherto in every trial the overall survival has been the same. So the story has grown up that it doesn't matter which treatment you try first, your overall outcome will be the same. Indeed there is a certain logic in trying the milder treatment first, because you may never have to try the more severe one. The other reason for choosing pfs is that the FDA tends to approve a drug combination if they can demonstrate an improvement in pfs.
There were also some secondary endpoints. It is important to name these as part of your intention to examine them, otherwise you can be accused of post-trial data dredging. This is the equivalent of shooting an arrow at a barn door and then drawing a target around where you hit and proclaiming that you have hit the target. The secondary endpoints were: overall survival, event-free survival, disease-free survival, duration of remission, time to new treatment of CLL or death, rates of molecular, complete, and partial remission, response rates and survival times in biological subgroups, rates of treatment related adverse effects, pharmaco-economic effect, and quality of life. Not all these results are reported in this paper.
What today's picture shows is that this was a well conducted trial. There were small numbers of drop-outs and non-compliant patients, but that is usual for such a trial and they did not affect the outcome.
3 comments:
It will be interesting to see how many more people die of Richter's transformation and myelodysplastic syndrome after taking this new 'gold standard'.
Let's face it; this is a retrospective trial using decades-old drugs. It exposes the patient to higher risks of terrible deaths from chemotherapy-related transformations.
Let the Germans have their militant regiment. I think the rest of the world can move on. There are SO many new drugs coming along, that suggest managing the disease without the genetic damage that FCR can inflict.
I'm beginning to agree with Dr. Furman, who has recently written that he believes it's better now to treat CLL as a chronic illness, and use milder drugs, than shoot for a home run that ends up killing the patient, without providing much of an over-all benefit.
I can remember when you were arguing the same thing, that chlorambucil was a good drug (even though it, too, is an alkylating agent), and these new-fangled drug combos such as FCR were promising more than they could deliver.
I'm not arguing that FR, or FCR, doesn't have it's place, but I wish that I would have reserved it just before a transplant, if necessary.
I'd like you to address the fact that once someone relapses from FCR, their prognosis is grim.
I see no mention of that in these postings.
This anonymouse sounds like Scott. I think that you had better wait until I finish this series of postings before you make these comments. I will certainly answer some of your concerns before I am finished. You are wrong though to talk about a retrospective trial, this was a prospective trial, and I don't think the word 'militant' is appropriate. I agree that this trial should have been done a decade ago, but you had better ask MDACC why it wasn't. The Germans are to be congratulated that it finally has been done. It has taken the 7 years to get this vital bit of information.
Dr. Kipps has told me that the Germans have a rigid mentality that hews the medical system into a non-flexible attitude. He told me of a trial following a fludarabine regime with Campath. In his opinion, it was given too close to the end of the chemotherapy. Patients fell like cordwood.
I do think that Germans have a reputation for authoritarian behavior. I recently read of one German emigre to the UK who on the whole liked working there, but he complained that the trains were often a bit late. That drove him nuts.
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