Oxygen tension in transplanted mouse osteosarcomas during fractionated high-LET- and low-LET radiotherapy--predictive aspects for choosing beam quality?

PURPOSE: The lower OER of high-LET radiations, compared to conventional (low-LET) radiations, has often been put forward as an argument for using high-LET radiotherapy in the management of hypoxic tumours. Among the different neutron beams used in therapy, the reactor fission neutrons have the lowest OER. The aim of the present study is to follow the variations of tumour oxygenation status during fractionated irradiation with different radiation qualities. Little information is available so far after fractionated high-LET irradiation. In addition, the RBE of reactor fission neutrons for effects on tumours and on normal tissues are compared.
MATERIAL AND METHODS: Murine OTS 64-osteosarcomas were transplanted in 102 balb-C mice and irradiated by 36 Gy of photons in fractions of 3 Gy five times a week (group P-36/3) or by 12 Gy of reactor fission neutrons in fractions of 2 Gy two times a week (group N-12/2). Irradiations started at a tumor volume of 500 to 600 mm3. A third group received no radiotherapy, but all investigations (group CG). Tumor volume and tumor oxygenation were measured once a week under therapy and during three weeks after therapy. For in vivo-evaluation of oxygen status a computerized polarographic needle electrode system (KIMOC pO2 histograph, Eppendorf) was used. The median pO2 and the hypoxic fraction (pO2 values < 5 mm Hg) of single tumors and of total groups were calculated from pooled histograms and from row data as well.
RESULTS: In correlation with the increase of tumor volume, from day 1 to day 42 of follow-up the median pO2 decreased from 20 mm to 8 mm Hg and the hypoxic fraction increased from 7% to 31%. After fractionated photon therapy a growth delay of three weeks was observed. Six weeks after beginning of the irradiation the median tumor volume had been doubled again. After fission neutron therapy growth delay continued until the end of the follow-up period. In both of the irradiated groups a significant decrease of median pO2 values and an increase of the hypoxic fraction were observed under radiotherapy. Hypoxia was more intensive after neutrons with a decrease of the median pO2 from 20 mm Hg to 1 mm Hg vs. 10 mm Hg after photon therapy and with an increase of the hypoxic fraction from 7% to 78% vs. 36% respectively. Two weeks after the end of therapy the median pO2 and the hypoxic fraction of both treated groups reached the levels prior to irradiation indicating a complete reoxygenation.
CONCLUSION: During fractionated irradiation of murine osteosarcomas with photons and reactor fission neutrons, a marked hypoxia was observed for both radiation qualities, but hypoxia was more intense during fractionated neutron irradiation. After irradiation, a complete reoxygenation occurred in both groups independently of the degree of hypoxia observed during the treatment. The RBE of reactor fission neutrons, after fractionated irradiation, was much higher for effects on murine osteosarcomas compared to their RBE observed for normal tissues in previous experiments. Present data are in agreement with our clinical observations on more than 300 patients treated with reactor fission neutrons for advanced and hypoxic tumours with various histologies.