CORRESPONDENCE

RESPONSE: Re: Measure Once or Twice—Does It Really Matter?

Susan G. Hilsenbeck, Daniel D. Von Hoff

Affiliations of authors: S. G. Hilsenbeck, Baylor College of Medicine, Houston, TX; D. D. Von Hoff, Arizona Cancer Center, The University of Arizona College of Medicine, Tucson.

Correspondence to: Daniel D. Von Hoff, M.D., Arizona Cancer Center, The University of Arizona College of Medicine, 1515 N. Campbell Ave., Tucson, AZ 85724-5024.

Thank you for the opportunity to reply and clarify.

In our editorial, we pointed out that the authors' assertion that "diameter is much more nearly proportional to the logarithm of cell number than is product" is a mathematically incorrect statement. We also pointed out that their Fig. 1, which they use to support their point, is misleading because of differences in the scales of the right- and left-hand axes. In their letter, we feel that they have missed the point of our comments. The mathematics of the situation has not changed. The logarithm of cell number is not linearly related to diameter, bidimensional product, or volume; it is linearly related to the logarithms of these quantities. So the question becomes, "which measure of tumor size is most linearly related to its own logarithm?" and the answer is, "they are all equally unrelated." James et al. go on to state in their letter that "proportional change in diameter performs well in estimating similar proportional changes in log cell kill." By this, we assume that they mean that doubling the diameter is roughly equivalent to doubling the logarithm of cell number. That is, doubling the diameter increases the volume, and therefore the number of cells, by a factor of 23 = 8. Doubling the logarithm of cell number [i.e., 2*log(cells)] is the same as squaring the number of cells. A 1-cm tumor with 109 cells would increase by a factor of 109, would weigh roughly 1 million kg, and would be the size of 10 blue whales. This assertion, of course, makes no sense. We tried to point this out in the editorial. While there is no theoretical basis for preferring diameter as a measure of tumor size, it is true that any bidimensionally defined response criteria can be translated into equivalent unidimensional criteria. The utility of such a switch from standard practice should be based on quality and reproducibility.

We were very interested to learn of the history of the RECIST working group and of the comparative analyses of several large pharmaceutical databases that confirm the results of James et al. We would, however, feel more comfortable if these analyses were accessible in a peer-reviewed forum and look forward to their publication. As we pointed out in the editorial, the authors' original definition of progression was associated with large increases in tumor size (30% increase in diameter implies a 120% increase in tumor volume), which might preclude effective second-line therapy. Apparently, the RECIST working group agreed, since they have adopted the more conservative definition of 20% increase in diameter, corresponding to a 73% increase in tumor volume. That is good news.

The authors' last point, implying that we recommended "randomized" studies, is a misrepresentation that we must correct. We recommended "prospective evaluation of their criteria, particularly the criteria for tumor progression." The word randomized was not included and is obviously not applicable.



             
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