Dosimetric comparison of bolus and continuous injections of CC49 monoclonal antibody in a colon cancer xenograft model

Abstract

Background: Improved understanding of dose and effective dose calculations may contribute to the optimization of fractionated radioimmunotherapy.

Methods: Comparison three-dimensional tumor dosimetry was performed on athymic nude mice bearing established LS174T human colon carcinoma xenografts. Mice were given bolus intraperitoneal injections of 300 microCi 131I-labeled CC49 monoclonal antibody once (Day 0) or three times (Days 0, 3, and 7) or continuous intraperitoneal infusion with miniosmotic pumps over 7 days. Serial section autoradiography was used to reconstruct tumor activity density distributions for Days 3, 4, 7, 10, and 11 (single injection); Days 3, 4, 7, 8, and 11 (3 injections); and Days 4, 7, 10, and 13 (pump). At least three tumors were reconstructed at each time point. Uptakes in blood and tumor were measured up to 14 days (single injection), 11 days (3 injections), or 16 days (pump) after injection.

Results: Average dose values calculated from total activity uptake data only (assuming no energy loss external to the tumor) yielded 102 Gy (single injection), 158 Gy (three injections), and 47 Gy (pump). Average doses using three-dimensional dose calculations were 88 Gy, 139 Gy, and 40 Gy, respectively. The nonuniformity of dose deposition affects treatment outcome, because cell loss is an exponential function of dose. Using the linear quadratic model with fractional cell survival to define an effective dose, D(eff) were calculated to be 20 Gy, 23 Gy, and 14 Gy, respectively. Cell proliferation affects outcome for variable dose-rate treatments. With cell proliferation parameters set to reproduce single-fraction 60Co recurrence results, D(eff) (for local control endpoint) were 8.9 Gy, 12.8 Gy, and 3.9 Gy, respectively. Three bolus injections compared with a single bolus injection were relatively less efficient in tumor uptake. However, three bolus injections resulted in a more uniform dose rate over a longer period, resulting in a 50% improvement in D(eff). The slower dose delivery for pump infusion resulted in a significantly lower D(eff), although dose-rate distributions were more uniform compared with the single bolus injection.

Conclusions: Improvement in dose-rate nonuniformities was observed for fractionated and continuous radiolabeled monoclonal antibody injections. Fractionated injections produced superior dosimetric results compared with single bolus or continuous injections.