Estimating the Risk for Secondary Cancer After Targeted α-Therapy with 211At Intraperitoneal Radioimmunotherapy

Abstract

Intraperitoneal ²¹¹At-based targeted α-therapy (TAT) may hold great promise as an adjuvant therapy after surgery and chemotherapy in epithelial ovarian cancer to eradicate any remaining undetectable disease. This implies that it will also be delivered to patients possibly already cured by the primary treatment. An estimate of long-term risks is therefore sought to determine whether the treatment is justified. Methods: Baseline data for risk estimates of α-particle irradiation were collected from published studies on excess cancer induction and mortality for subjects exposed to either ²²⁴Ra treatments or Thorotrast contrast agent (25% ThO₂ colloid, containing ²³²Th). Organ dosimetry for ²²⁴Ra and Thorotrast irradiation were taken from the literature. These organ-specific risks were then applied to our previously reported dosimetry for intraperitoneal ²¹¹At-TAT patients. Results: Risk could be estimated for 10 different organ or organ groups. The calculated excess relative risk per gray (ERR/Gy) could be sorted into 2 groups. The lower-ERR/Gy group, ranging up to a value of approximately 5, included trachea, bronchus, and lung, at 0.52 (95% CI, 0.21-0.82); stomach, at 1.4 (95% CI, -5.0-7.9); lymphoid and hematopoietic system, at 2.17 (95% CI, 1.7-2.7); bone and articular cartilage, at 2.6 (95% CI, 2.0-3.3); breast, at 3.45 (95% CI, -10-17); and colon, at 4.5 (95% CI, -3.5-13). The higher-ERR/Gy group, ranging from approximately 10 to 15, included urinary bladder, at 10.1 (95% CI, 1.4-23); liver, at 14.2 (95% CI, 13-16); kidney, at 14.9 (95% CI, 3.9-26); and lip, oral cavity, and pharynx, at 15.20 (95% CI, 2.73-27.63). Applying a typical candidate patient (female, age 65 y) and correcting for the reference population mortality rate, the total estimated excess mortality for an intraperitoneal ²¹¹At-monoclonal antibody treatment amounted to 1.13 per 100 treated. More than half this excess originated from urinary bladder and kidney, 0.29 and 0.34, respectively. Depending on various adjustments in calculation and assumptions on competing risks, excess mortality could range from 0.11 to 1.84 per 100 treated. Conclusion: Published epidemiologic data on lifelong detriment after α-particle irradiation and its dosimetry allowed calculations to estimate the risk for secondary cancer after ²¹¹At-based intraperitoneal TAT. Measures to reduce dose to the urinary organs may further decrease the estimated relative low risk for secondary cancer from ²¹¹At-monoclonal antibody-based intraperitoneal TAT.

Keywords: astatine-211; human; radium-224; secondary cancer; targeted α-therapy; α-particle.

Graphical abstract

FIGURE 1.

Pooled ERR/Gy for different organs or organ groups with 95% CI. Data for bladder represent only 1 background study (Nekolla et al. 2009 (10)).