Inter- and intra-tumor heterogeneity on Gallium-68 DOTATATE/DOTATOC PET/CT predicts response to Lutetium-177 DOTATATE PRRT in Neuroendocrine Tumor Patients

Introduction: Overall tumor heterogeneity across metastatic lesions can determine time to progression (TTP) and overall survival (OS) in NET patients undergoing PRRT; this was evaluated on pre-therapy somatostatin receptor PET/CTs.

Methods: In retrospective study on the NET patients treated with ¹⁷⁷Lu-DOTATATE, PET metrics of tumor burden such as SUVmax, somatostatin receptor expression, and tumor volume as well as indices of tumor heterogeneity for each lesion (intra-tumor) and across all lesions throughout the body (inter-tumor) were evaluated on the pre-PRRT somatostatin receptor PET/CT. Inter-tumor heterogeneity was calculated through a suggested novel methodology for summarization of values across the lesions. Endpoints included combined post-PRRT clinical and imaging TTP, and OS. Cox regression models were used to assess the predictive capability of the imaging variables on post-PRRT TTP and OS.

Results: TTP and OS were evaluated in patients who completed more than one cycle of PRRT (78 patients). The most common adverse symptoms were fatigue/tiredness (78.2%), diarrhea (50.0%), nausea/vomiting (45.4%), and abdominal pain (42.3%). Estimated 9-month and 36-month combined clinical and imaging progression free rates were 72% (95% CI: 60-81%) and 16% (95% CI: 8-27%), respectively. The estimated 36-month OS was 69% (95% CI: 54-79%). Among the 53 imaging variables analyzed to evaluate the disease extent and tumor heterogeneity, none of the values showed significant prediction of combined clinical and imaging TTP. On univariable analysis, Mean coefficient of variation of SUV of the lesions across the body was predictive of survival (concordance = 0.64, p=0.04) with increasing values associated with better survival. Several other imaging indices of tumor heterogeneity showed borderline statistical significance with increasing values being associated with a tendency for increased survival.

Conclusions: Inter- and intra-tumor heterogeneity may predict the response to ¹⁷⁷Lu-DOTATATE. Larger scale multicenter trials can be conducted to further prove the clinical utility of the novel methodology applied in this exploratory study.