Patient-Specific Dosimetry-Driven PRRT: Time to Move Forward!

TO THE EDITOR: Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-labeled somatostatin analogs is a well-established radiopharmaceutical therapy for neuroendocrine tumors. Its high efficacy, associated with limited toxicity, led to its approval by regulatory authorities based on phase III randomized clinical trials that used fixed administered activities and number of cycles (1,2). For various reasons, therapy optimization based on dosimetry is not yet routinely implemented (3). However, several recently published articles have demonstrated a correlation between tumor-absorbed dose and clinical outcomes (such as progression-free survival and overall survival) in patients with gastroenteropancreatic neuroendocrine tumors treated with [¹⁷⁷Lu]Lu-DOTATATE according to the current standard and approved protocol (7.4 GBq × 4 administrations at fixed intervals).

Mileva et al. (4) reported that an optimal absorbed dose cutoff of 35 Gy in all target lesions after the first cycle of PRRT (C₁) discriminated patients with a significantly longer median progression-free survival (48.1 mo) than that of patients in whom at least 1 target lesion was treated with less than 35 Gy in C₁ (26.2 mo).

Hebert et al. (5) found that patients with a cumulative absorbed dose greater than 91.4 Gy had a median progression-free survival of 39.4 mo, compared with 23.6 mo for those who received less than 91.4 Gy. Patients with at least 1 lesion receiving less than 52.5 Gy at treatment end presented shorter overall survival.

Maccauro et al. (6) found that global mean absorbed dose after C₁ and global mean cumulative absorbed dose cutoffs of 10.6 and 43 Gy, respectively, were significantly associated with prolonged progression-free survival (>45.5 and 42 mo vs. 21 mo).

The similarity in the conclusions of the aforementioned articles, yet obtained in an independent manner, is indeed astonishing. Therefore, it appears essential to deliver a minimum absorbed dose to achieve survival benefits. Despite their inherent heterogeneity, these articles agree in demonstrating a strong absorbed dose–efficacy relationship.

This letter is a “call to arms” for a multidisciplinary cooperation.

Accurate data interchange among centers would enable appropriate comparison of the obtained values. This is a task addressed to physicists, requiring them to process data from the same patients using different workflows to identify meaningful dosimetry indices (minimum, maximum, median absorbed doses, etc.).

Meanwhile, physicians should perform a clinical analysis of the baseline characteristics of the cohort selected for each study to assess the extent to which the clinical conclusions drawn can be applied to other cohorts. This would include data regarding the studied populations (stage, grade, primary site location, previous lines of treatment, etc.) but also the way the response and side effects are assessed.

To achieve statistically meaningful outcomes while balancing feasibility and efficacy, physicians and physicists should work with scientific societies to design prospective, multicenter, randomized interventional trials. We specifically recommend dosimetry-driven, 2-arm trials, with 1 arm focused on maximizing tumor-absorbed doses—by increasing the number of 7.4 GBq cycles, shortening the interval between cycles, or increasing the injected activity per cycle—while closely monitoring dosimetry and toxicity parameters for organs at risk.

• © 2025 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication November 24, 2024.
• Accepted for publication December 5, 2024.