Full-Body Tumor Response Heterogeneity of Metastatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radiopharmaceutical Therapy

Abstract

Patients with metastatic neuroendocrine tumors (NETs) can present with hundreds of lesions, and each lesion might have a unique response pattern to peptide receptor radiopharmaceutical therapy (PRRT). This response heterogeneity has been observed but is poorly understood. In this work, we perform a quantitative analysis of longitudinal PET/CT scans to comprehensively characterize the NET response to PRRT. Methods: NET patients treated with [¹⁷⁷Lu]Lu-DOTATATE PRRT imaged at baseline, during, and after PRRT with [⁶⁸Ga]Ga-DOTATATE PET/CT were enrolled in this retrospective single-institutional study. A deep-learning model was used to identify and contour regions of nonphysiological elevated tracer uptake (lesion-regions of interest [ROIs]). An automated analysis was performed to identify, contour, and quantify the individual lesion-ROI uptake, match ROI between time points, and categorize each lesion-ROI as disappearing, decreasing (ΔSUV_total < -30%), stable (-30% ≤ ΔSUV_total ≤ 30%), increasing (ΔSUV_total > 30%), or new. A patient was considered to have response heterogeneity if both new or increasing lesion-ROIs and decreasing or disappearing lesion-ROIs were present after therapy. Results: Eighteen patients who received between 2 and 7 [⁶⁸Ga]Ga-DOTATATE PET/CT scans were enrolled. In total, 3,289 lesion-ROIs were contoured in the 67 scans acquired (median of 24 lesion-ROIs per image), and 1,459 lesion-ROI tracks, defined as the path that each unique lesion-ROI follows across all time points, were determined by the ROI tracking method (median of 49 tracks per patient). All patients presented with disease response heterogeneity at the first follow-up scan. All 10 patients with more than 1 follow-up scan showed nonmonotonic change in lesion-ROI uptake. Of 129 tracks containing new lesion-ROIs at the first follow-up, 80 (62%) eventually resolved on final follow-up, whereas only 12% (7/60) of the tracks with lesion-ROIs disappearing at the first follow-up scan returned on final follow-up. Conclusion: To the best of our knowledge, this is the first study to evaluate response comprehensively and quantitatively in terms of individual lesion-ROIs. Response heterogeneity was observed in 100% of the patients, which suggests that comprehensive, lesion-level, response assessment is vital for the accurate understanding of the NET response to PRRT.

Keywords: PET/CT; neuroendocrine tumor; peptide receptor radiopharmaceutical therapy; response heterogeneity; theranostics; treatment response assessment.