Influence of scheduling, dose, and volume of administration of a perfluorochemical emulsion on tumor response to radiation therapy

Abstract

Studies were carried out with a new, concentrated perfluorochemical emulsion (PFCE) of the perfluorochemical F44E (48% V/V). When given at 4, 1.6, or 1 g/kg in undiluted injection volumes iv 1 hr prior to a range of single doses of radiation with inspired carbogen dose modifying factors (DMF's) based on tumor growth delay (TGD) in the Lewis lung tumor of 2.5, 1.7, and 1.5, respectively, were produced. When the PFC dose was administered in a volume of 0.2 ml, the dose modifying factors produced by 4 g/kg (0.1 ml undiluted) did not change significantly (2.6), but the dose modifying factors produced by 1.6 g/kg (0.04 ml undiluted) and by 1.0 g/kg (0.025 ml undiluted) increased significantly to 2.0 and 1.8 ( p < 0.05), respectively. Using the tumor excision assay at 24 hr post treatment in the FSaIIC fibrosarcoma, administration of 6, 4, or 2 g/kg in 0.2 ml injections plus carbogen breathing l hr prior to and during treatment resulted in dose modifying factors of 1.5, 1.6, and 1.3, respectively. In a fractionated radiation protocol in the Lewis lung tumor using four daily fractions, a dose of 4 g/kg of PFC on days 1 and 3 proved superior to a dose of 2 g/kg daily (dose modifying factors 2.4 vs. 1.9, p < 0.05). When a fractionated radiation regimen of 3 Gy daily × 5 and carbogen was used, PFC doses of 0.5, 1, 2, and 4 g/kg administered undiluted produced increasing tumor growth delays with increasing dose of PFCE and increasing frequency of administration. In addition, dilutions to 0.2 ml proved significantly more effective. In a 2-week fractionated radiation protocol using 2, 3, or 4 Gy daily × 5 weekly, PFCE given in 0.2 ml volume plus carbogen breathing daily at 4, 1.6, or 1 g/kg produced dose modifying factors of 2.0, 1.9, and 1.6, respectively. Finally, when used in a day 1, 3, and 5 radiation regimen for 3 weeks at 2, 3, or 4 Gy/fraction, 4 g/kg of PFCE given in a volume of 0.2 ml plus carbogen breathing produced a superior dose modifying factor (1.6) as compared with 1.6 or 1.0 g/kg (dose modifying factors 1.4 and 1.3, respectively). These results indicate that PFCE plus carbogen breathing effectively enhances the antitumor effects of both single dose and fractionated radiation. In addition, a significant effect of volume of administration was demonstrated which suggests that some of the efficacy of this perfluorochemical emulsion plus carbogen may be dependent on changes in circulatory dynamics which result in increases in tumor perfusion.