Heterogeneity in Somatostatin-Receptor(SSTR-)PET/CT can Predict Response to Radiopeptide Therapy and Overall Survival in Patients with SSTR-expressing Tumors - a Multicenter Retrospective Trial

Objectives Pretherapeutic somatostatin receptor (SSTR)-PET/CT is mandatory to confirm adequate SSTR density for peptide receptor radionuclide therapy (PRRT). The Phase 3 NETTER-1 trial demonstrated significantly improved Progression-Free Survival (PFS) for 177Lu-DOTATATE in comparison to Octreotide LAR in advanced midgut neuroendocrine tumor (NET). These encouraging results emphasize the need for of reliable tools for response prediction in appropriate PRRT candidates. In this multicenter trial, we aimed to evaluate the prognostic value of tumor heterogeneity as assessed by SSTR imaging in patients with NET.

Methods 142 patients with SSTR-expressing tumors (71 females, mean age, 62.7 ± 11.2 y) at 4 German university medical centers were retrospectively analyzed. All patients obtained SSTR-PET/CT before start of PRRT (2-6 cycles depending on the response in imaging after each two cycles). Metastatic lesions were delineated manually; if more than three bone, lymph node or soft tissue metastases were present only the three largest were evaluated for each category. After manual segmentation of 872 metastases using the Interview Fusion Workstation (Mediso Inc., Budapest, Hungary), conventional parameters and textural features analyzing 30 different parameters were investigated. All parameters were correlated with time to progression (TTP) and overall survival (OS) in addition a Cox-proportional-hazards regression was performed. Parameters with significant correlation were examined by receiver operating characteristic (ROC) analysis to obtain cut-off values to be used for Kaplan-Meier analysis. In addition, an analysis for bone, lymph node and soft tissue metastases was performed separately.

Results 75 patients showed progression (mean PFS 595 days) and 54 patients died (mean OS 723 days) after the PET/CT examination. For correlation with TTP, mean and max SUV as conventional parameters and just “SKEWNESS” as textural parameter showed statistical significance. For OS, mean and max SUV as conventional parameter correlated significantly whereas 3 textural parameters (SKEWNESS, CORRELATION and COV) showed statistical significant correlation. ROC analysis showed significant prognostic capability of the OS for CORRELATION; the Kaplan-Meier analysis showed significant prognostic capability for CORRELATION to predict OS as well, whereas a low CORRELATION is a worse prognostic factor (figure). The additional analysis for bone, lymph node and soft tissue metastases did not show any significant difference.

Conclusions Tumor heterogeneity assessed by SSTR-PET/CT showed prognostic value for patients with SSTR-expressing tumors which show higher significance than conventional PET parameters. Thereby, in a “theranostic” approach, non-invasive assessment of textural features offers the opportunity for risk stratification in potential PRRT candidates and may be included in further prospective studies. Figure: Kaplan-Meier plots and number-at-risk tables for probability of overall survival. Low-risk group (solid lines) was identified by the textural parameter CORRELATION. Cut-off values derived by ROC analysis were used.

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