September 23, 1999

Comments on Dr. McGuire's "Counterpoint" in Physician's Weekly:

This is really a marvelous example of how the opinion leaders just don't get it.

In the first place, Dr. McGuire's comments on evaluability rates are germane only to the old "Human Tumor Cloning" assay. With the cell death/apoptotic assays we use, the assay non-evaluability rate is not 40%; it is less than 5%.

Second, Dr. McGuire goes to great lengths to prove that in vitro assays are not perfect scale models of chemotherapy in the patient. Of course they are not.

The way that the assays work is as follows. Tumor cells are exposed to a panel of drugs under rigorously standardized conditions, chosen to produce the maximum scatter (highest standard deviation) of results among a universe of tumor specimens. The hypothesis is that drugs which are active in vitro under these standardized conditions are more likely to work than drugs which are not active in vitro. This is a perfectly ordinary hypothesis. Yet it is supported by extraordinary data. Over 40 consecutive published studies prove that this hypothesis is true. When patients are treated with drugs which are active in vitro in cell death (apoptotic) assays, they are 9 times more likely to respond than when they are treated with drugs which are not active in vitro. And they live significantly longer. The correlation between in vitro and clinical is not perfect - probably for reasons such as those given by Dr. McGuire. But the correlation is highly useful. Given a choice between drug(s) which have an 1X chance of working and a 9X chance of working, in most cases most people would prefer to receive the 9X drugs and avoid the 1X drugs.

As for the clinical trials Dr. McGuire and others want to see, why won't he and others support these trials? Several years ago I helped write a protocol for Dr. McGuire's own cooperative group (the Gynecologic Oncology Group). I offered to perform the tests at my own expense. But the cooperative group refused to perform the trial. As have many other cooperative groups. As has the NCI. We have a 95% assay-evaluability rate and have assay systems designed and proven to identify active drugs and combinations (not merely inactive drugs). These assays are saving and prolonging lives today in the real world. But Dr. McGuire and others would hold these assays hostage to a hypothetical series of clinical trials which they have never had any willingness to support. The last patients to enjoy the benefit of cell culture drug resistance testing will be those patients cared for in cooperative groups and NCI-designated cancer centers. It is perhaps the greatest lost opportunity in all of clinical cancer research.

- Larry Weisenthal