Relationship between potential doubling time ( Tpot), labeling index and duration of DNA synthesis in 60 esophageal and 35 breast tumors: is it worthwhile to measure Tpot?

Abstract

Background: In recent years T pot (potential doubling time) has been measured before treatment in human tumors in an attempt to estimate the proliferation taking place during a course of irradiation. T pot is defined as T s/ LI, where T s is the duration of DNA synthesis and LI is the labeling index (proportion of cells synthesizing DNA). T s is more difficult to measure than LI, so the question arises whether variation introduced during the determination of T s is compensated by the theoretically better relevance of the quotient T pot than of LI alone. It is not clear from comparisons with clinical outcome whether T pot is a useful indicator of proliferation or whether LI is more prognostic, as suggested by a currently ongoing multicenter analysis elsewhere. Therefore, we investigated intercomparisons between T pot and its components LI and T s in two in their proliferation rates contrasting types of tumor where multiple biopsies were taken from each tumor. Materials and methods: Sixty patients with esophageal carcinoma and 57 patients with breast cancer were included in this study. All patients were injected with IUdR 6–8 h before surgery. From each tumor three to five biopsies were taken at surgery. Using flow cytometry, LI and T s were measured on all biopsies in order to calculate T pot. Logarithmic transformations of the distributions were used to examine correlations. Kappa-tests were used to assess how reliable an LI value could be in predicting the corresponding T pot. Results: T s and LI were not completely independent, based on the within-tumor coefficients of variation ( CV w). The ratio of between-tumor coefficient of variation ( CV b) to the CV w suggested that the discriminative power of T pot was higher than LI for esophagus, but the reverse in breast tumors, which had a larger range. Pearson correlation coefficients were high for log T pot versus log LI in both types of tumor, but the predictive power was low, as shown by κ-values of only 0.3–0.41 starting with LI and trying to predict the corresponding value of T pot. Increasing widths of a central `gray zone' were investigated for improved discrimination between fast and slow proliferation. Multiples of the within-tumor standard deviation, equally on each side of the median, were used to vary the width of the gray zone. Without a gray zone no more than 70% successful matching was obtained in esophagus tumors, compared with 80% in breast tumors. However, by excluding about half of the esophageal tumors an 80% success rate was achieved. In breast tumors over 90% matching was obtained more easily, keeping 80% of the tumors classifiable. For both tumor types correlations between T s and T pot were weak, with a trend towards short T s associated with short T pot and also with low LI. The latter correlation was significant for esophageal tumors and resulted in T pot values having a smaller range than the LIs. Conclusion: Although there were good correlation coefficients between T pot and LI, the predictive power of either from the other was not reliable, except by excluding a significant number of tumors close to the medians. The predictive value of LI for T pot was higher for breast tumors because the spread in cell kinetic measurements was wide. Until more clinical data become available on outcome in comparison with LI or T pot, it is still worthwhile to measure T pot and to assess the prognostic value of both LI and T pot in relation to outcome.