Tumor growth rate as a metric of progression, response, and prognosis in pancreatic and intestinal neuroendocrine tumors

Abstract

BackgroundLanreotide depot/autogel antitumor activity in intestinal/pancreatic neuroendocrine tumors (NETs) was demonstrated in the phase-3 CLARINET study (NCT00353496), based on significantly prolonged progression-free survival (PFS) versus placebo.MethodsDuring CLARINET, patients with metastatic intestinal/pancreatic NETs received lanreotide depot/autogel 120 mg or placebo every 4 weeks for 96 weeks. Imaging data (response evaluation criteria in solid tumors [RECIST] v1.0, centrally reviewed) were re-evaluated in this post hoc analysis of tumor growth rate (TGR) in NETs. TGR (%/month) was calculated from two imaging scans during relevant periods: pre-treatment (TGR0); 12–24 weeks before randomization versus baseline; each treatment visit versus baseline (TGRTx-0); between consecutive treatment visits (TGRTx-Tx). To assess TGR as a measure of prognosis, PFS was compared for TGR0 subgroups stratified by optimum TGR0 cut-off; a multivariate analysis was conducted to identify prognostic factors for PFS.ResultsTGR0 revealed tumors growing during pre-treatment (median [interquartile range] TGR0: lanreotide 2.1%/month [0.2; 6.1]; placebo 2.7%/month [0.15; 6.8]), contrary to RECIST status. TGR was significantly reduced by 12 weeks with lanreotide versus placebo (difference in least-square mean TGR0–12 of − 2.9 [− 5.1, − 0.8], p = 0.008), a difference that was maintained at most subsequent visits. TGR0 > 4%/month had greater risk of progression/death than ≤4%/month (hazard ratio 4.1; [95% CI 2.5–6.5]; p < 0.001); multivariate analysis revealed lanreotide treatment, progression at baseline, TGR0, hepatic tumor load, and primary tumor type were independently associated with PFS.ConclusionsTGR provides valuable information on tumor activity and prognosis in patients with metastatic intestinal/pancreatic NETs, and identifies early lanreotide depot/autogel antitumor activity.Trial registrationRetrospective registration, 18 July 2006; EudraCT: 2005–004904-35; ClinicalTrials.gov: NCT00353496.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5257-x) contains supplementary material, which is available to authorized users.

Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients’ Outcome in Neuroendocrine Tumors (NET)—The GREPONET Study

“…Receiver operating characteristic (ROC) curves and logistic regression were employed for identification of the most informative TGR first and TGR 3m cutoffs for prediction of 12 month progression rate. For TGR 0 , a previously identified cutoff of 4%/m was employed for survival analysis . Comparison of this cutoff with other alternative cutoffs identified by median and ROC analyses was performed.…”

“…Emerging data suggest that TGR could be of value in patients with GEP‐NETs; the Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET) study evaluated lanreotide versus placebo in nonfunctioning small intestinal or pancreatic NETs with a Ki67 of <10 % . After 12 weeks of treatment, almost all patients achieved stable disease on RECIST (lanreotide, 90/96 patients; placebo, 94/98 patients).…”

Salvage PRRT with 177Lu-DOTA-octreotate in extensively pretreated patients with metastatic neuroendocrine tumor (NET): dosimetry, toxicity, efficacy, and survival

“…The highest increase in incidence is observed in localized and Grade I NET [1]. However, metastatic disease is observed in 20–40% of NET patients at initial diagnosis and has a significant impact on survival [2–4]. The over-expression of somatostatin receptors (SSTR) on the cell surface of NET [5] provides a theragnostic approach using radiolabeled somatostatin analogs such as 68 Ga-DOTA-D-Phe-Tyr3-octreotate ( 68 Ga-DOTATATE) for positron emission tomography / computed tomography (PET/CT) imaging and the β-emitter 177 Lu-DOTA-D-Phe-Tyr3-octreotate ( 177 Lu-DOTATATE) for peptide receptor radionuclide therapy (PRRT), which established as a safe and effective therapy option in metastatic, well-differentiated NET [6–8].…”

Systemic Treatment Selection for Patients with Advanced Pancreatic Neuroendocrine Tumours (PanNETs)

“…Firstly, the assessment of tumour response to therapy remains challenging in NETs. Significant improvement in response assessment in patients with PanNETs have been made, moving away from using clinical/biological responses to the use of validated WHO (World Health Organization) and RECIST (Response Evaluation Criteria in Solid Tumours) criteria [146]. In addition, more sensitive and specific nuclear imaging techniques visualising SSTR expression (111In-SPECT, 68-GaPET/CT) may be used for the diagnosis and assessing response to therapy beyond RECIST.…”

“…Combining different imaging technologies and assessment of disease with cross-sectional and molecular imaging is increasingly relevant for patients with PanNETs, not only for treatment selection following a theranostic approach, but also for assessment of response to therapy [143,144]. The development of novel radiological assessment strategies may also be of help (i.e., alternative cut-off definitions for assessment of response [145] or assessment of Tumour Growth Rate (TGR) [123,146,147].…”