E L S E V I E R

Int. J. Radiation Oncology Biol. Phys., Vol. 35, No. 3, pp. 633-634, 1996 Copyright © 1996 Elsevier Science Inc. Printed in the USA. All rights reserved

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• Editorial

W H A T Tpo T IS NOT

H. RODNEY WITHERS, M.D., D.Sc.

Department of Radiation Oncology and JCCC, UCLA, Los Angeles, CA 90095

The reader should not draw an important wrong conclu- sion from the article "Potential Doubling Time and Clini- cal Outcome in Head and Neck Squamous Cell Carci- noma Treated with 70 Gy in 7 Weeks" by Bourhis et al. ( 1 ). Their results show that measured values of potential doubling time (Tpo0 were not useful for predicting local relapse among 70 patients with tumors of the oropharynx treated in the same overall time of 7 weeks. The authors did not conclude that this absence of such a correlation signified a lack of accelerated repopulation in tumors during treatment, and neither should the reader.

Tpot describes the rate at which a tumor cell population ( tumor volume) might double if the whole tumor was proliferating at the rate measured for the subpopulation comprising the growth fraction. Growth fractions vary, but biologists think in terms of about 20% for a plain run-of-the-mill tumor. Thus, if the average tumor cell cycle time was 1 day and the growth fraction 20%, then Tpot would be 5 days. But, at least in normal tissues, the most important determinant of repopulation and, in fact, the only absolute requirement for the start of repopulation in a steady-state tissue, is a change in the cell loss pattern. In steady-state normal tissues, such as epithelial surfaces, bone marrow, etc., the cell loss factor is 1.0; that is, each mitotic division results, on average, in one new clono- genic cell and one cell lost by differentiation, apoptosis, shedding, or whatever and, by definition, the doubling time is infinite. Obviously, the cell loss factor must be less than 1.0 in a growing tumor. But, in an epithelial tumor doubling every 2 months and characterized by a Tpot value of 4 days, the cell loss factor is not much less than 1.0.

The rate of tumor growth can be accelerated by three mechanisms: an increase in the growth fraction, a shorten- ing of the cell cycle, and a reduction in the cell loss factor. Even if the growth fraction changed abruptly from 20 to 100%, the result would be only an immediate one-time fivefold increase of clonogens in cycle, that is, an effect slightly more than that of two doublings. The cell cycle

time is unlikely to shorten by much more than a factor of two (and probably less), which would double the rate of growth. But, analysis of results of radiation therapy suggest that rates of repopulation in head and neck tumors reflect a ten- to twentyfold decrease in doubling times. It seems likely that a substantial decrease in the cell loss factor is a major determinant of repopulation kinetics in irradiated tumors (as it is in normal tissues).

Tpo, does not measure the cell loss factor, even though cell loss is necessary to maintain a low growth fraction. Thus, it would be fortuitous if Tpo t w e r e to prove useful as a predictive assay for accelerated regrowth during cyto- toxic therapy, a point that has always been recognized by the proponents of its use. The main reason for optimism that it might have been a useful predictor of accelerated repopulation was that most estimates for Tpo t in human tumors ranged around 3 to 5 days, similar to the estimate for clonogen doubling rates late in radiotherapy for head and neck cancers.

It is disappointing that Tpo t may not prove as useful as we had hoped. Not that a study of 70 patients is definitive evidence for failure, especially given that values of Tpo , from multiple biopsies within the same tumor may show a wide range, and that other factors, such as T and N stage, played a big role in responses. But, others are beginning to reach a similar conclusion.

To predict which tumors are more likely to escape local control as a result of accelerated growth of residual tumor clonogens during radiation therapy, we need tests that will predict two characteristics; the lag time before accelerated growth begins (T~,g or Tbag ) and the doubling rate, thereaf- ter. If we assume that these responses, especially the lag time, are determined by a cytokine-mediated feedback response to the development of injury in the tumor (cell lysis), as it is in normal tissues, something as difficult as measuring accurately the rate of regression (volume reduction) of the tumor may prove a good predictor. The quicker the regression, the earlier the onset of accelerated regrowth. Because rate of regression will be highest in

Accepted for publication 29 March 1996.

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634 I.J. Radiation Oncology • Biology • Physics Volume 35, Number 3, 1996

tumors with a fast cell turnover rate, measurements of labeling index, apoptotic index, or rate of loss of radioac- tively labeled tumor cells may also prove helpful. Note, however, that labeling index is already a parameter in- cluded in estimates of Tpot and also was not, of itself, useful in the present study.

One of the major reasons for developing assays for pre- dicting rapid regrowth is to enable the selection of patients for accelerated treatment regimens, even though the poten- tial for therapeutic gain from this strategy is commonly limited by acute normal tissue toxicity. Other, perhaps easier ways may emerge for predicting individual tumor repopula-

tion responses, allowing some rational flexibility to be intro- duced into prescribing dose intensities. However, it is not necessary to predict the kinetic behavior of tumors to avoid 4azanecessary protraction of overall treatment time, and its attendant reduction in tumor control probability. Although it is important to strive to improve on current outcomes, an easier and more compulsory goal is avoiding worsened outcomes. Thus, it is reemphasized that the lack of predictive value of T~,~ in the study by Bourhis et al. ( 1 ) should not be misinterpreted as an absence of accelerated repopulation in treated tumors, and a reason for treating at less than maximum tolerated dose intensities.

REFERENCES

1. Bourhis, J.; Dendale, R.; Hill, C.; Bosq, J.; Fortin, A.; Martindale, C.; Mamelle, G.; Julieron, M.; Marandas, P.; Schwaab, G.; Wibault, P.; Malaise, E. P.; Luboinski, B.; Eschwege, F.; Wilson, G. Potential doubling time and clini-

cal outcome in head and neck squamous cell carcinoma treated with 70 Gy in 7 weeks. I. J. Radiat. Oncol. Biol. Phys. 35(3):471-476; 1996.