Surrogate markers

A recent Cochrane review of trials comparing fludarabine and alkylating agents (such as chlorambucil) as first line treatment for CLL found no difference in overall survival. In a meta-analysis of five trials randomizing 1838 patients there was no significant difference. What is more, it is highly likely that however many trials are done and however long we wait, we will never find a difference.

In my opinion there will be no more trials comparing fludarabine with alkylating agents. For one thing these trials take so long to do. The successor to CLL4 was projected to last 11 years. Even the MRC, which is committed to staying the course, jibbed at that. Pharmaceutical companies, who must see a return on their investment before the patent runs out, are not going to consider such trials. Another reason is the fact that you don’t just get treated once for CLL. When you relapse there is something else to try, and with the number of new agents in the pipeline there will be things to try even if you were to relapse 10 years down the line.

I want to draw your attention to an abstract at the forthcoming ASH meeting in Orlando.

This is abstract # 304 from Daniel Catovsky, Monica Else, Sue Richards, Peter Hillmen: The Lack of Survival Differences in Randomized Trials in CLL May Be Related to the Effect of Second Line Therapies. A Report from the LRF CLL4 Trial.

“We conclude from this analysis that the likely reason for the lack of (overall) survival differences in CLL4 and in other CLL trials relates directly to the better responses and improved survival rates after second line treatment in those receiving the less effective therapy first, i.e. chlorambucil (or fludarabine) in CLL4.”

What they are saying is that CLL differs from acute leukemia where the response to the first course of treatment determines the outcome. It has even been suggested that you can tell from a bone marrow biopsy 6 days after chemotherapy for acute leukemia whether the patient is going to be a long term survivor. If there is any leukemia left the patients will do badly. However, it seems to be the case that it doesn’t matter whether you give fludarabine or chlorambucil first, because you will able to get a good response second time around.

They go on to say:

“Our findings support the view that PFS (progression-free survival) and quality of life should be used when assessing new treatment modalities in CLL, while continuing to evaluate survival differences to ensure that there is no adverse effect.”

Those who design clinical trials in CLL have accepted that overall survival cannot be used as an end-point except in patients who have had several rounds of treatment and have a short life expectancy. These other end-points, PFS and QOL (quality of life), are known as surrogate end points.

I won’t say much about quality of life in this essay. For one thing it is very difficult to measure – one man’s meat is another man’s poison, but also CLL4 has so far shown no difference in QOL. It seems to be the case that patients in remission have a better QOL than patients in relapse, but whether that still holds good when you push chemotherapy to get a deeper remission has yet to be evaluated.

As far as PFS is concerned a salutary lesson was learned from a study in myeloma published earlier this year in the New England Journal of Medicine. The study from Little Rock examined the effect of thalidomide on patients having so called ‘total therapy’ ‘Total therapy’ means two autologous stem cell transplants. It had already been established that giving thalidomide after the second transplant prolonged life, so the obvious question was whether giving thalidomide from the beginning of treatment was even better. Sure enough, there was a higher response rate and a longer progression-free survival in those who had the long-term thalidomide. But overall survival was the same.

Now taking thalidomide is no picnic. It causes constipation, sleepiness and peripheral neuropathy. So the conclusion of the trial was that more thalidomide meant more side-effects but no more life.

Surrogate markers are useful if they really do translate into extra life or at least a better quality of life, but otherwise they give a false sense of security.

All we know from all these trials is that fludarabine is an active agent in CLL, with about as much activity as alkylating agents. When oncologists find two agents that are both active in a disease, which neither cures, the next thing we do is combine them. Next time I will write about combinations.