Efficacy and safety of ²²⁵Ac-DOTATATE targeted alpha therapy in metastatic paragangliomas: a pilot study

In this study, we aim to evaluate the efficacy and safety of ²²⁵AC-DOTATATE targeted alpha therapy in advanced-stage paragangliomas (PGLs).

Nine (6 males and 3 females) consecutive patients with histologically proven PGLs were treated with ²²⁵Ac-DOTATATE targeted alpha therapy (TAT) and concomitant radiosensitizer, capecitabine, at 8-weekly intervals up to a cumulative activity of ~ 74 MBq. The primary endpoint included evaluating therapy response and disease control rate (DCR) using the RECIST 1.1 criteria. Additional secondary endpoints comprised clinical response assessment using EORTC QLQ-H&N35 questionnaire, Karnofsky Performance Scale (KPS), Eastern Cooperative Oncology Group performance status (ECOG), analgesic score (AS), dose alterations of anti-hypertensive drugs (anti-HTN), and the safety and side-effect profile evaluation as per CTCAE criteria version 5.0.

Following ²²⁵Ac-DOTATATE treatment, morphological response revealed partial response in 50%, stable disease in 37.5%, and disease progression in 12.5%, with a DCR of 87.5%. Similarly, the symptomatic response was remarkable, and anti-HTN drugs were stopped in 25% and reduced in 37.5%. Another significant finding in our study revealed a morphologic DCR of 66.6% (2/3) in patients who failed previous lutetium-177 peptide receptor radionuclide therapy (¹⁷⁷Lu-PRRT). Regarding the KPS, ECOG, and AS performance scores, a notable improvement was observed post-²²⁵Ac-DOTATATE treatment. The QLQ-H&N35 symptom scores evaluated in seven H&N PGL patients showed significant improvement in all aspects. No improvement in sexual function was noted (P = 0.3559). Despite the significant reduction in the analgesic score post-treatment (P = 0.0031), the QLQ-H&N35 revealed only marginal significance concerning the intake of pain killers (P = 0.1723). No grade III/IV hematological, renal, and hepatological toxicities were noted.

The evidence from this study suggests ²²⁵Ac-DOTATATE therapy is effective and safe in the treatment of advanced-stage PGLs and also reports a clear benefit even in patient’s refractory to the previous ¹⁷⁷Lu-PRRT.