Modeling killing and repopulation kinetics of subclinical XXXX : direct calculations from clinical data.

@entity0 @entity138 @entity5 @entity3 @entity151
PURPOSE: Models for cell killing and repopulation can provide insight into the efficacy of therapies. Using clinical data on @entity0 recurrence after lumpectomy with or without radiotherapy (L+/- @entity138 ) and brain @entity3 after chemotherapy with or without prophylactic cranial irradiation (C+/-PCI) for @entity151 , estimates of cell killing and subclinical repopulation were tested against the results from simple radiobiologic models. METHODS AND MATERIALS: The rates of local @entity0 recurrence after L+/- @entity138 and of brain @entity3 after C+/-PCI were extracted from published randomized trials. In Method 1, assuming simple exponential growth, the cell number distributions after L+/- @entity138 and C+/-PCI were calculated from the clinical data, and the impact of @entity138 on these distributions was determined. In Method 2, "classic" radiobiology dictates that a typical course of breast @entity138 and PCI results in approximately =7 and approximately =4.5 log of cell kill, respectively. Using an assumption of uniform log-kill, the clinical doubling times (CDTs) can be calculated directly from the clinical data. RESULTS: Using Method 1, for @entity0 and assuming a CDT of 110 days and a clinically detectable cell number of 10(9), the calculated cell number distribution would be approximately uniformly distributed from 1 to 10(8) cells, with @entity138 reducing the frequency at all points by approximately =75%. From the brain metastasis data, assuming a CDT of 55 days, a cell number distribution of 10(3) to 10(8) cells would be calculated. PCI reduces the frequency of @entity3 by roughly 40%. For both the breast and the brain data, the effects of @entity138 on the cell number distribution are not consistent with uniform radiosensitivity. Using Method 2, assuming a cell number of 10 after L+/- @entity138 , the calculated CDTs range from 14 to 124 days. For the brain metastasis case, assuming a starting cell number of 3.16 x 10(3), the CDTs would primarily be in the 10-30-day range. CONCLUSION: The distribution of clinical responses to adjuvant @entity138 suggests a broad range of radiosensitivity, rather than uniform log cell kill. The subpopulation of @entity5 with minimal cell kill appears to be significant. This heterogeneity may be due to radioresistant subpopulations, failure to irradiate @entity5 cells, and/or new @entity5 formation. Similarly, the computed CDTs consistent with the clinical data are shorter than those reported in the literature. Simple radiobiologic models that fail to incorporate heterogeneity of radiosensitivity and/or @entity5 cell repopulation do not adequately describe clinical outcomes.
