Is there a future for cell kinetic measurements using IdUrd or BdUrd?

Abstract

Purpose: The analysis of causes of radiation failure both in retrospective series of patients with head and neck cancer and in several randomized clinical trials suggests a loss of local control as the overall treatment time increases for the same total dose. This is attributed to tumor cell proliferation during fractionated radiotherapy. As longer treatment times lead to loss of local control, it has been suggested that shorter treatment times could lead to an increase in local control. For this reason accelerated treatment regimens have been and are being designed. However, these treatments may cause severe acute reactions. Due to this, lower total doses are sometimes given. Slowly proliferating tumors, therefore, may do worse when treated with accelerated schedules compared with conventional schedules. In addition, it is not desirable to subject all patients to the more intense acute reactions of accelerated schedules. It would thus be useful to predict which tumors will rapidly proliferate during treatment and are likely to benefit from accelerated radiotherapy. The potential doubling time (Tpot) is defined as the time within which the cell population of a tumor would double if there were no cell loss. The hypothesis is that the median Tpot measured before treatment might correlate with the effective doubling time (Tp) during treatment. Conclusion: Tpot can be calculated knowing the labeling index (LI; proportion of cells incorporating the DNA precursor IdUrd or BdUrd) and Ts (the DNA synthesis time) measured by flow cytometry. A recent multicenter analysis has shown that the only pretreatment kinetic parameter for which some evidence is found for an association with local control is LI, not Tpot. Pitfalls associated with cell kinetic measurements such as assay variability, intratumor and intertumor variability, interlaboratory variability and the problem of an admixture of normal and malignant cells make Tpot not accurate and reproducible enough for a robust predictive assay. It therefore appears that pretreatment Tpot measurements using flow cytometry, provide only a relatively weak predictor of outcome after radiotherapy in head and neck cancer. Immunohistochemistry allows a simple measure of LI and may give additional independent information from labeling patterns, suggesting that this method is the (short term) future for clinical cell kinetic measurements using BdUrd or IdUrd.