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 continuous low-dose-rate (LDR) irradiation by either single-dose or fractionated high-dose-rate (HDR) irradiation. In this study, the equivalence of LDR treatments and fractionated HDR (2 fractions/day) or pulsed-dose-rate (PDR, 4 fractions/day) schedules in terms of tumor cure was investigated in an experimental tumor model. METHODS AND MATERIALS: Tumors (rat rhabdomyosarcoma R1M) 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 geometry. HDR was given using an (192)Ir single-stepping source. To investigate 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 given in 1 or 2 fractions per day, TCD(50)-values were substantially lower than that for LDR. A PDR schedule with an interfraction interval of 3 h (4 fractions/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 between 2 or 4 fractions/day. Catheter implantation alone decreased the TCD(50) for single-dose ERT already by 17.4 Gy. Cell viability assessed at 24 h after treatment demonstrated an increased 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 long intervals, the sparing effect of sublethal damage repair may be significantly counteracted by reoxygenation. During 3-h intervals, however, repair may be largely completed with only partial reoxygenation causing PDR schedules to be less effective than fractionated HDR, and equivalent to LDR. Brachytherapy with clinically sized fractions after a large external top-up dose showed a remarkable increase in tumor control rate with no effect of fractionation (up to 4 fractions/day), which could not be fully explained by differences in dose distribution or in the cell viability assessed after treatment. This suggests a longer lasting effect on cell survival or radiosensitivity associated with catheter implantation shortly after the top-up dose.

Tumor hypoxia--a confounding or exploitable factor in interstitial brachytherapy? Effects of tissue trauma in an experimental rat tumor model.

PURPOSE: To evaluate the potential effects of tumor hypoxia induced by afterloading catheter implantation on the effectiveness of brachytherapy in a rat tumor model. METHODS AND MATERIALS: Afterloading catheters (4) were implanted in subcutaneously growing R1M rhabdomyosarcoma in female Wag/Rij rats. A MicroSelectron (Nucletron) was used for interstitial high-dose-rate irradiation ((192)Ir). Tumor oxygenation, perfusion, and cell survival were assessed by pO(2) histography (Eppendorf), Tc-99m injection, and excision assay, respectively. RESULTS: Tumor perfusion was markedly reduced at 1 h after catheter implantation (33.9 +/- 6.0% (SEM, n = 9) of control) and partly recovered after 5 h (61.5 +/- 12.2%). At 24 h, the perfusion level reached control values (100.6 +/- 25.7%), but was highly variable with some of the tumors showing hardly any recovery at all. Tumor oxygenation showed a similar pattern, but with less recovery. Median pO(2) readings were 13.5, 1.2, and 5.3 mm Hg before and at 1 and 24 h after implantation, respectively (7 tumors). The percentages of pO(2) readings

Effect of age on radiation-induced early changes of rat rectum. A histological time sequence.

BACKGROUND AND PURPOSE: Radiation treatment of the elderly (> 75 years) is often modified due to an assumed decrease in normal tissue tolerance in this age group. Since more radiobiological data concerning normal tissue toxicity as a function of age are needed, a histological study of age-related radiation changes of the rectum was performed. MATERIALS AND METHODS: The rectum of young and old female Wistar rats (12 and 78 weeks, respectively) was irradiated with single doses of 22 and 39 Gy. The field size was 1.5 x 2.0 cm. The animals were sacrificed at 1, 2, 4 and 10 weeks after treatment. To evaluate radiation damage, 12 histological parameters were scored in four areas of the rectum. A total radiation injury score was calculated. The number of proliferative epithelial cells was evaluated by 5-bromo-2'-deoxyuridine labeling. RESULTS: Some age-related histological differences were observed; especially, the incidence of ulceration and vascular occlusion was higher in the older group. In the low dose group of the older animals, 60% showed ulceration, which was 0% for the young low dose animals. Severe vascular changes occurred early and were more extensive in older animals (4 weeks) than in the younger group (10 weeks). In the area adjacent to the treatment field, cell proliferation increased significantly in older rats at 1 week after 22 Gy, which did not occur in the young group. CONCLUSIONS: Discrete radiation-induced histological differences were observed between the rectum of young and old Wistar rats, especially in the development of ulceration and vascular changes. Although the survival of these Wistar rats in earlier studies was not affected by age, the impact of the observed histological differences for their importance in the long-term is currently being investigated.

A 27 MHz current source interstitial hyperthermia system for small animals.

Temperature distribution is an important factor in thermo-radiotherapy and it is greatly dependent on the applied heating technique. Consistency of the heating method is therefore important in translating in vivo experimental data to the clinical situation. To further evaluate the combination of interstitial hyperthermia and interstitial radiotherapy, an experimental interstitial hyperthermia system has been developed for small (500-2000 mm3) tumours growing in the flank of a rat. The system used reproduces the properties of our clinical current source interstitial hyperthermia system. The heating system consists of four applicators, each with independent tuning and power control. The applicators are situated inside plastic afterloading catheters and are capacitively coupled with the surrounding tissue. The tumour is heated through dissipation of a 27 MHz current flowing to an external ground plane. An effective RF-filter allows reliable thermocouple temperature measurements when the power is switched on. The tumour temperature is easily controlled by means of a continuous temperature read-out and a clear temperature display. A minimum temperature up to 46 degrees C can be reached within 4-10 min and maintained (+/-0.5 degrees C) throughout the treatment period. Modelling calculations performed for this heating system indicate that the applicator temperatures should be kept equal in order to minimize the difference between maximum and minimum temperature. Significantly higher applicator currents are needed at larger distances from the ground plane. In addition, the homogeneity of the temperature distribution is improved when either the tumour is isolated or when the environmental temperature is increased. The calculations also show that temperature distribution is strongly dependent on effective heat conductivity. A description of the system and its performance is presented.

Interstitial hyperthermia and interstitial radiotherapy of a rat rhabdomyosarcoma; effects of sequential treatment and consequences for clonogenic repopulation.

Animal tumour experiments have been performed to elucidate the interactions between interstitial hyperthermia (IHT) and interstitial radiotherapy (IRT), and to obtain information about the most effective sequence of these treatment modalities. Experimental tumours, transplanted in the flank of Wag/Rij rats, were treated with IHT for 0.5 h at 44 degrees C, and with IRT using low dose-rate (LDR) iridium-192 sources. Both tumour cure probability and the fraction of clonogenic cells in vitro after different IHT and IRT treatments in vivo, were used as endpoints. The sequence of a short (0.5 h) IHT treatment followed by an extended LDR-IRT treatment lasting up to 10 days appeared to be very effective, and resulted in a significant thermal enhancement ratio of 1.34 at the 50% tumour cure probability level. A not significantly increased thermal enhancement of 1.06 was found when the same IHT treatment followed IRT. The level of clonogenic cell survival after IHT alone is high (0.24 +/- 0.08) compared with that after an IRT dose of 20 Gy (0.017 +/- 0.004). Clonogenic cell repopulation started 2-4 days after the in vivo treatment irrespective of the type of treatment. The in vivo combination of IHT and LDR-IRT resulted in lower surviving fractions compared with IRT alone, regardless of the time interval between the end of treatment and in vitro clonogenic assay. IHT followed by LDR-IRT appeared to be the most effective treatment in terms of tumour cure. The in vivo/in vitro studies indicated that the effect of hyperthermia is mainly attributed to radiosensitization, possibly by partial inhibition of sublethal damage repair processes during the subsequent irradiation. The hyperthermia-induced cytotoxicity was of minor importance as estimated from the surviving clonogenic fraction.