Objective:

To report a case of hyperprogressive disease (HPD) potentially induced by zoledronic acid in a patient with RET-driven neuroendocrine carcinoma undergoing treatment with selpercatinib, highlighting its significance in clinical practice.

Key Findings:

• The patient achieved partial remission with selpercatinib and denosumab but developed HPD after switching to zoledronic acid, with serum NSE levels rising from 29.2 ng/mL to 282 ng/mL.
• Significant increases in tumor burden were observed after the introduction of zoledronic acid, with rapid clinical deterioration.
• The patient's condition deteriorated rapidly, resulting in death 8 months post-diagnosis.

Interpretation:

The case suggests a potential triggering role of zoledronic acid in HPD, although causality remains unproven, indicating a need for careful monitoring in clinical practice.

Limitations:

• Causality between zoledronic acid and HPD is speculative and requires further investigation, particularly considering the financial constraints that influenced treatment decisions.
• Alternative explanations for tumor aggressiveness and resistance to selpercatinib were not definitively ruled out.

Conclusion:

Switching bone-modifying agents during RET inhibitor therapy necessitates close monitoring; further studies are needed to explore the safety and mechanisms of HPD, particularly in the context of financial constraints.