Intraperitoneal α-Emitting Radioimmunotherapy with 211At in Relapsed Ovarian Cancer: Long-Term Follow-up with Individual Absorbed Dose Estimations

Abstract

Eliminating microscopic residual disease with α-particle radiation is theoretically appealing. After extensive preclinical work with α-particle-emitting ²¹¹At, we performed a phase I trial with intraperitoneal α-particle therapy in epithelial ovarian cancer using ²¹¹At conjugated to MX35, the antigen-binding fragments-F(ab')₂-of a mouse monoclonal antibody. We now present clinical outcome data and toxicity in a long-term follow-up with individual absorbed dose estimations. Methods: Twelve patients with relapsed epithelial ovarian cancer, achieving a second complete or nearly complete response with chemotherapy, received intraperitoneal treatment with escalating (20-215 MBq/L) activity concentrations of ²¹¹At-MX35 F(ab')_2.Results: The activity concentration was escalated to 215 MBq/L without any dose-limiting toxicities. Most toxicities were low-grade and likely related to the treatment procedure, not clearly linked to the α-particle irradiation, with no observed hematologic toxicity. One grade 3 fatigue and 1 grade 4 intestinal perforation during catheter implantation were observed. Four patients had a survival of more than 6 y, one of whom did not relapse. At progression, chemotherapy was given without signs of reduced tolerability. Overall median survival was 35 mo, with a 1-, 2-, 5-, and 10-y survival of 100%, 83%, 50%, and 25%, respectively. Calculations of the absorbed doses showed that a lower specific activity is associated with a lower single-cell dose, whereas a high specific activity may result in a lower central dose in microtumors. Individual differences in absorbed dose to possible microtumors were due to variations in administered activity and the specific activity. Conclusion: No apparent signs of radiation-induced toxicity or decreased tolerance to relapse therapy were observed. The dosimetric calculations show that further optimization is advisable to increase the efficacy and reduce possible long-term toxicity.

Keywords: alpha particle; astatine; intraperitoneal; ovarian cancer; phase I.

FIGURE 1.

Histogram depicting on which day adverse events resolved as grouped by grade. Majority (85%) of adverse events resolved within 2 wk. Six adverse events that resolved between weeks 3 and 7 were skin-related, for example, port infection.

FIGURE 2.

Correlations between time to progression (TTP, mo) and activity concentration (MBq/L), specific activity (²¹¹At/mAb), single-cell dose (Gy), and 10-Gy isodepths (μm) to 200- and 300-μm spheres showing no significant associations. nb = number.