Estimation of Maximum Cumulative Administered Activity for Radiopharmaceuticals in Early Clinical Trials: Assessing...

External beam radiation therapy-derived tolerance doses for long-term radiation toxicity (eg, 23 Gy kidney limit) are routinely applied to radioligand therapy (RLT) for dosage selection in clinical trials. However, these thresholds are independent of the RLT molecule or patient populations, potentially leading to inaccurate toxicity assessments and suboptimal treatment.

Normal tissue complication probability (NTCP) curves were extrapolated from external beam radiation therapy to RLT using the biologically effective dose (BED). Population level toxicity risk was then calculated by integrating the NTCP over the absorbed dose distribution in the organ at risk. The long-term risk observable in a population with a limited life expectancy was further estimated as the cumulative incidence function. The method was applied to kidney absorbed dose data from the Erasmus MC clinical study of ¹⁷⁷Lu-DOTATATE. Simulations assessed the impact of absorbed dose variability and patients' life expectancy on toxicity risk and on the maximum cumulative activity, with sensitivity analysis on radiobiological and NTCP parameters.

In 414 Erasmus MC patients, the mean kidney dose was 19 ± 5 Gy, with no treatment-related kidney failures during a median 78-month follow-up. The nephropathy risk estimated using BED was only 0.6%. Simulations showed toxicity risk depends on both mean dose and variability; a 5% 5-year nephropathy risk corresponded to 22 Gy BED at a 50% coefficient of variation versus 32 Gy at a 15% coefficient of variation. A 20% higher administered activity with the same risk could be administered in hypothetical patient population with 12-month survival compared to the Erasmus MC study population with 63 months survival. Radiobiological and NTCP parameter variations minimally affected maximum dose estimates.

The interindividual variability in kidney dosimetry and life expectancy in the treated population impact long-term toxicity risk at given cumulative activity. Accounting for these factors may enable more accurate estimation of toxicity risk and selection of administered activity, improving the risk-benefit balance.