125 In vitro assays for predicting tumor cell response to radiation by apoptotic pathways

Purpose/Objectlve: To e.~timat e the magnitude of the dose adiu~tnlents that could potentially be made if radiotherapy doses were tailored to the individual patient using a predictive a~ssay of normal-tissue radiosensitivity Materials de; Methods: A (Ionogenic assay was used to estimate the surviving fraction at 2 Cy (SF2) for fibroblast cultures derived from skirl biopsies of 9-6 ra.di~therapy patients.Late react~on~ i~ skin.subcutaneous tissue, mucous membrane, b~ne, znd larynx in the s~me patients were scored from grade 0 to 4 using the RTOG/EORTC grading system.:['he doses to these tissues were estimated from CT scans and converted to the equivalent total dose given e,s 2 Gy pet fraction (D2) to allow comparisons between doses from different fractionation regimens.The incidence of severe (grade 3 or 4) late reactions in each tissue was analyzed as a function of both dose (D2) and radiosensitivity (SF2) Fitted response models were then used to estimate the changes in dose that would be required in each individual patients to limit the incidence of severe late complications.Results: There was a clear influence of t~oth dose (D2) and radiosensiti~ ity !SF2) on the incidence of severe late normal-tissue reactions among these p~tients.Grad," :/ a~td 4 complications occurred ex~ }uaive~y amp,it patients for whom the flbroblast SF2 was near or below average (5F2 = 0.36), and the incidence of severe complications was particularly high among the patients with the smatlest values of SFL near SF2 = 20%.The dose effect was dependent on radiosensitivity: among patients with SF2 in the average range (0.3 to 0.4), severe reactJons occurred only m tissues receiving more than 63 Gy, wherea~ late complications occurred after doses as low as 50 Gy in patients with SF2 < 30% An example of the dose adjustments that could F,e made on the basis of individual radiosensitivity is provided by considering late reactions in skin and subcutaneous tissue.All patients experiencing a severe reaction in either of these two tissues were estimated to be at 36% or higher risk because of their small SF2 values ~ lose to 0.2), despite the relatively low doses they received (_< 56 Oy).To lower the risk to 5% among the~e patients, an average dose reduction of 9 T CRy I range 3.1 to 21.9 Gy) would have been required.In contrast, 2/a of patients ,~'ith SF2 values ~ 0.3 were a{.5% or lowe~ risk of severe r(-actions m these tissues.The doses to these patients could have been increased by an average of 10.8 Gv (range 0.5 to 44.7 (3v) without e×ceeding the 5~ risk level.[f doses were adjusted to reach a uniform 5% risk of severe reactions in skin or subcutaneous tissue irl all I)ar:ients, the number and magnitude of the dose increases would outweigh those of the dose reductions Thus ii is estimated that the overall local tumor control rate would increase as a result of individualized dose adjustments. Conclusions:The results 01 this study supporl the concept that a predictive assay of normal-tissue radiosensivity could effectively be used to select the treatmer)t dose for individual patients 1 here is a su}~set o{ re~J~taJ~t patients {or whom very large increases in dose, from 10 Oy up to perhaps [~0 or 40 Gy. are predicled to he possible withou~ a >ignifi~ant morea,so in [ate complications.For these ye.tlerits, ~ significant therapeutic gain could be ach,,wed.