Extinction of the weakest

Purpose: To examine whether changes in the effective doubling time of tumor cells during irradiation of Fe-ad-and-neck cancer are linked to accumulati ng dose. Methods and Materials: Optimal fitting of the results of four apparently is o-effective regimens in three recently reported randomized controlled trial s (continuous hyperfractionated accelerated radiation therapy [CHART], Radi ation Therapy Oncology Group [RTOG] 90-03, and Trans-Tasman Radiation Oncol ogy Group [TROG] 91.01) was attempted using two different types of model of the change in effective doubling time that may occur during treatment. The first involved the traditional approach where doubling time changes at spe cific times after the start of treatment regardless of fractionation used ( "fixed response time" models). The second is where changes in doubling time are linked to accumulating biologic dose ("cellular depletion" models). Results: Changes in effective doubling time occur during radiotherapy for h ead-and-neck cancer. Data from the fh-ree trials can be fitted successfully by functions that imply a continuous reduction in effective doubling time. Models linking the reductions in effective doubling time to the cellular d epletion that occurs in the tumor during radiotherapy fit the data satisfac torily. Effective doubling time ultimately reduces to 2 days, or slightly l ess, during high-dose radiotherapy regimens designed to cure squamous head- and-neck cancer. Conclusions: If the assumption of iso-effectivity is justified then this st udy indicates that the "repopulation phenomenon" may be best described by a function that depicts a reduction in effective tumor cell doubling time th at decreases continuously during treatment down to a certain minimum value. Furthermore, this reduction may be linked to cellular depletion. (C) 2001 Elsevier Science Inc.