Sunday, May 15, 2011

The difficulties of assessing response in trials

One of the problems with clinical trials is that their interpretation is so subjective. Having spent a couple of years as part of an independent review panel looking at the outcome of a clinical trial I confess that I have found some of the decisions very difficult.

For example, to obtain a complete remission in CLL it is necessary for all evidence of the disease to disappear, but that is not enough. It is also necessary for the blood count to be restored to normal. It is not necessary to have the disappearance of the disease to be confirmed by CT or US scan, but it is necessary to demonstrate that there are fewer than 30% of lymphocytes in a bone marrow trephine. If for some reason there has been a CT scan or an US then far from making matters easier, they become more difficult.

If someone has simply been examined clinically then one has to feel the lymph nodes in neck, armpit and groin and note that none of them has a long diameter of greater than 1.5 cm - not easy to be sure if the patient is fat. Liver and spleen are measured in cm below the margin of the ribs. If, after treatment, no lymph nodes or liver or spleen can be felt then there is a chance of a complete remission. But if a scan is done we have to make a decision as to whether what we have imaged is normal tissue or abnormal and usually this is not possible. How large is a normal spleen? It is bigger for men than women and I take a longest diameter of 10 cm for women an 12 cm for men. But obviously it varies between individuals. Is 13 cms an enlarged spleen? If it has reduced from 19 cm is it a complete remission?

Livers are even more difficult. They can be enlarged in leukemia for other reasons than disease infiltration. Seldom do they return to a mid-axillary length of 12 cm after treatment. CT scans make things difficult. But if CT scans are not done there is a danger of missing important large retroperitoneal lymph nodes.

Bone marrow trephines post-chemotherapy are essential if there could be a CR. There has been a tendency to do bone marrow aspirates and look for minimal residual disease by flow cytometry, but this cuts no ice with those who are doing the assessing, even though it might be a more accurate and meaningful way of adjudicating on response. For a CR there must be fewer than 30% lymphocytes in the marrow trephine. Obviously we don't count every cell so someone makes an estimate. This is seldom done very accurately; someone just gives his best shot. Even if there are fewer than 30% the trephine must be free of nodules, since nodules are incalculable. If there are nodules then a CR becomes a nodular PR.

The bone marrow trephine must be normo- or hypercellular. If it is not, it must be repeated in 4 weeks. I can tell you that this is an instruction that is rarely fulfilled.

The net result is that when the rules are applied strictly there are few CRs and when they are not, the CRs that are declared cannot be trusted.

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