EANM expert opinion: How can lessons from radiobiology be applied to the design of clinical trials? Part I: back to the basics of absorbed dose-response and threshold absorbed doses.

Purpose: This study by the EANM radiobiology working group aims to analyze the efficacy and toxicity of targeted radionuclide therapy (TRT) using radiopharmaceuticals approved by the EMA and FDA for neuroendocrine tumors and prostate cancer. It seeks to understand the correlation between physical parameters such as absorbed dose and TRT outcomes, alongside other biological factors.

Methods: We reviewed clinical studies on TRT, focusing on the relationship between physical parameters and treatment outcomes, and applying basic radiobiological principles to radiopharmaceutical therapy to identify key factors affecting therapeutic success.

Results: The analysis revealed that mean absorbed dose alone is insufficient to predict treatment response or toxicity. For absorbed doses below a certain threshold, outcomes are unpredictable, while doses above this threshold improve the likelihood of biological responses. However, even at higher absorbed doses, response plateaus indicate the need for additional parameters to explain outcome variability, including heterogeneity in target expression, anatomical disease location, (epi)genetics, DNA repair capacity, and the tumor microenvironment, aspects that will be discussed in Part II of this analysis.

Conclusion: Understanding radiobiology is crucial for optimizing TRT. More dosimetric data is needed to refine treatment protocols. While absorbed dose is critical, it alone does not determine TRT outcomes. Future research should integrate biological parameters with physical dosimetry to enhance efficacy and minimize toxicity.