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Purpose: Tumor growth rate (TGR) represents the percentage change in tumor volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR 3m ) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in neuroendocrine tumors (NET)., Experimental Design: Patients from 7 centers with advanced grade (G) 1/2 NETs from the pancreas (P)/small bowel (SB) initiating ST/WW were eligible. Computed tomography (CT)/MRI performed at prebaseline, baseline, and 3(±1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (ΔTGR 3m-BL ; paired T test), and Aim-2: validate TGR 3m (<0.8%/m vs. ≥0.8%/m) as an early biomarker in an independent cohort (Kaplan-Meier/Cox regression)., Results: Of 785 patients screened, 127 were eligible. Mean (SD) TGR 0 and TGR 3m were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean (SD) ΔTGR 3m-BL paired-difference was -6.8%/m (19.3; P < 0.001). Most marked ΔTGR 3m-BL [mean (SD)] were identified with targeted therapies [-11.3%/m (4.7); P = 0.0237] and chemotherapy [-7.9%/m (3.4); P = 0.0261]. Multivariable analysis confirmed the absence of previous treatment (OR = 4.65; 95% CI, 1.31-16.52; P = 0.018) and low TGR 3m (continuous variable; OR 1.09; 95% CI, 1.01-1.19; P = 0.042) to be independent predictors of radiologic objective response. When the multivariable survival analysis for PFS (Cox regression) was adjusted to grade ( P = 0.004) and stage ( P = 0.017), TGR 3m ≥ 0.8 (vs. <0.8) maintained its significance as a prognostic factor ( P < 0.001), whereas TGR 0 and ΔTGR 3m-BL did not. TGR 3m ≥ 0.8%/m was confirmed as an independent prognostic factor for PFS [external validation; Aim-2; multivariable HR 2.21 (95% CI, 1.21-3.70; P = 0.003)]., Conclusions: TGR has a role as a biomarker for monitoring response to therapy for early identification of treatment-induced changes and for early prediction of PFS and radiologic objective response., (©2019 American Association for Cancer Research.)