Dose escalation of amifostine for radioprotection during pelvic accelerated radiotherapy.
OBJECTIVE
Experimental data suggest a dose-dependent efficacy of amifostine so that the low overall doses used in clinical trials may have masked the full potential of the drug. In this study, we report our experience with the role of escalated doses of amifostine in the protection of pelvic tissues.


METHODS
A total of 354 patients with pelvic carcinomas recruited in prospective protocols applying hypofractionated and accelerated radiotherapy (HypoARC) supported with escalated daily doses of amifostine (0, 500, 750, 1000 mg subcutaneously) were analyzed. Conformal pelvic radiation delivered 14 daily fractions of 2.7 Gy within 18 days, whereas booster techniques increased the daily fraction to the target area to 3.4 Gy.


RESULTS
Using a dose-individualization algorithm, 55.4% tolerated a daily amifostine dose of 1000 mg (level 3), 15.9% of 750 mg (level 2), and 17.5% of 500 mg (level 1), whereas intolerance induced amifostine interruption in 11.3% of the patients. Early grade 2/3 urinary frequency and dysuria grades 1 to 2 were significantly higher in level 0 patients (P = 0.04 and 0.01, respectively). The dose level (1 to 3) of amifostine did not influence the incidence of frequency/dysurea. Acute diarrhea and proctitis grade 2/3 were significantly lower only in level 3 (P < 0.0001 and 0.03, respectively). Dose level 3 was also linked to reduced incidence of late bladder and intestinal toxicities (P<0.05). Local control analysis showed no tumor protection effect of amifostine.


CONCLUSIONS
Higher amifostine doses are tolerable by patients with pelvic malignancies and can better protect pelvic tissues against early and short-term late effects of radiotherapy.
Department of Radiotherapy/Oncology, Medical Schools, Democritus University of Thrace, Alexandroupolis, Greece. targ@her.forthnet.gr
Michael I
MI
Koukourakis
George
G
Kyrgias
Marianthi
M
Panteliadou
Aikaterini
A
Papadopoulou
Maria
M
Tsiarkatsi
Eli
E
Papachristou
Maria
M
Bebeli
D000328:Adult; D000368:Aged; D004999:Amifostine / Q000627:therapeutic use*; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010386:Pelvic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D011446:Prospective Studies; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D020266:Radiotherapy, Conformal / Q000009:adverse effects / Q000379:methods; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
D011837:Radiation-Protective Agents; D004999:Amifostine