Equivalence of hyperfractionated and continuous brachytherapy in a rat tumor model and remarkable effectiveness when preceded by external irradiation

Purpose: In clinical brachytherapy, there is a tendency to replace continuo us low-dose-rate (LDR) irradiation by either single-dose or fractionated hi gh-dose-rate (HDR) irradiation. In this study, the equivalence of LDR treat ments and fractionated HDR (2 fractions/day) or pulsed-dose-rate (PDR, 4 fr actions/day) schedules in terms of tumor cure was investigated in an experi mental tumor model. Methods and Materials: Tumors (rat rhabdomyosarcoma RIM) were grown s.c. in the flank of rats and implanted with 4 catheters guided by a template. All interstitial radiation treatment (IRT) schedules were given in the same ge ometry. HDR was given using an Ir-192 single-stepping source. To investigat e small fraction sizes, part of the fractionated HDR and PDR schedules were applied after an external irradiation (ERT) top-up dose. The endpoint was the probability of tumor control at 150 days after treatment. Cell survival was estimated by excision assay. Results: Although there was no fractionation effect for fractionated HDR gi ven in 1 or 2 fractions per day, TCD50-values were substantially lower than that for LDR. A PDR schedule with an interfraction interval of 3 h (4 frac tions/day), however, was equivalent to LDR. The combination of ERT and IRT resulted in a remarkably increased tumor control probability in all top-up regimens, but no difference was found beteeen 2 or 4 fractions/day. Cathete r implantation alone decreased the TCD50 for single-dose ERT already by 17. 4 Gy. Cell viability assessed at 24 h after treatment demonstrated an incre ased effectiveness of interstitial treatment, but, after 10 Gy ERT followed by 10 Gy IRT (24-h interval), it was not less than that calculated for the combined effect of these treatments given separately. Conclusion: In full fractionation schedules employing large fractions and l ong intervals, the sparing effect of sublethal damage repair may be signifi cantly counteracted by reoxygenation. During 3-h intervals, however, repair may be largely completed with only partial reoxygenation causing PDR sched ules to be less effective than fractionated HDR, and equivalent to LDR. Bra chytherapy with clinically sized fractions after a large external top-up do se showed a remarkable increase in tumor control rate with no effect of fra ctionation (up to 4 fractions/day), which could not be fully explained by d ifferences in dose distribution or in the cell viabilily assessed after tre atment. This suggests a longer lasting effect on cell survival or radiosens itivity associated with catheter implantation shortly after the top-up dose . (C) 2001 Elsevier Science Inc.