Estimating the risk for secondary cancer following targeted alpha therapy with astatine-211 intraperitoneal radioimmunotherapy.

Intraperitoneal 211 At-based targeted alpha therapy (TAT) may hold most promise as an adjuvant therapy following surgery and chemotherapy in epithelial ovarian cancer to eradicate any remaining undetectable disease. This implies it will also be delivered to patients possibly already cured by the primary treatment. An estimate of long-term risks is therefore sought whether to justify the treatment. Methods: Baseline data for risk estimates of alpha-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 for our previously reported dosimetry for intraperitoneal (i.p.) 211 At-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 two groups. In the lower ERR/Gy group, up to approx. 5, were: Trachea, bronchus and lung 0.52 (CI 95% 0.21-0.82), Stomach 1.4 (CI 95% -5.0-7.9), Lymphoid and hematopoietic system 2.17 (CI 95% 1.7-2.7), Bone and articular cartilage 2.6 (CI 95% 2.0-3.3), Breast 3.45 (CI 95% -10-17) and Colon 4.5 (CI 95% -3.5-13). In the higher ERR/Gy group, ranging from approx. 10 to 15 were: Urinary bladder 10.1 (CI 95% 1.4-23), Liver 14.2 (CI 95% 13-16), Kidney 14.9 (CI 95% 3.9-26) and Lip, oral cavity and pharynx 15.20 (CI 95% 2.73-27.63). Applying a typical candidate patient (female, age 65 years) and correcting for reference population mortality rate, a total estimated excess mortality of an i.p. 211 At-mAb treatment amounted to 1.13 per 100 treated. More than half of 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 - 1.84 per 100 treated. Conclusion: Published epidemiological data on life-long detriment following alpha-particle irradiation and its dosimetry allowed calculations to estimate the risk for secondary cancer following 211 At-based i.p. TAT. Measures to reduce dose to the urinary organs may further decrease the estimated relative low risk for secondary cancer from 211 At-mAb based i.p. TAT.