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. 2019 Jan 14;19(1):66.
doi: 10.1186/s12885-018-5257-x.

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

Clarisse Dromain  1 , Marianne E Pavel  2 , Philippe Ruszniewski  3   4 , Alison Langley  5 , Christine Massien  5   6 , Eric Baudin  7 , Martyn E Caplin  8 ; CLARINET Study Group
Collaborators, Affiliations

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

Clarisse Dromain et al. BMC Cancer. .

Abstract

Background: Lanreotide 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.

Methods: During 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.

Results: TGR0 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.

Conclusions: TGR provides valuable information on tumor activity and prognosis in patients with metastatic intestinal/pancreatic NETs, and identifies early lanreotide depot/autogel antitumor activity.

Trial registration: Retrospective registration, 18 July 2006; EudraCT: 2005-004904-35; ClinicalTrials.gov: NCT00353496 .

Keywords: Lanreotide; Neuroendocrine tumor; Prognostic factor; RECIST; Tumor growth rate.

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Conflict of interest statement

Ethics approval and consent to participate

Trial documentation was approved by institutional review boards at each study site, and all patients provided written informed consent. A full list of the ethics committees and their institutions is provided in Appendix 1 of the Additional file 1.

Consent for publication

Not applicable

Competing interests

CD: Consultant/Advisor: Ipsen; MEP: Consultant/Advisor: Ipsen, Lexicon, Novartis, Pfizer; Research Support: Ipsen, Novartis; PR: Consultant/Advisor: Ipsen; Speakers bureau: Ipsen, Novartis; Research Support: Ipsen, Novartis; Employee: Ipsen (Spouse); AL: Employee: Ipsen; CM: Employee: Ipsen (at the time of work); EB: Received remuneration for services (advisory board or board of directors; corporate-sponsored research; consulting fee; research investigator; speaker) from Ipsen, Novartis, Pfizer, and Advanced Accelerator Applications; MEC: Received honoraria, consultancy and speakers’ bureau fees from Ipsen, Advanced Accelerator Applications, and Novartis.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Distribution of (a) TGR0 and (b) percentage change in SLD among patients during the pre-treatment period. a Distribution of TGR0 among patients during the pre-treatment period according to RECIST v1.0 classification. Individual data points represent the TGR0 in individual patients (ITT population), according to their classification by RECIST v1.0. Boxes represent median and interquartile range (Q1–Q3), whiskers represent the minimum observation still within 1.5 IQR of lower quartile (Q1), and the maximum observation still within 1.5 IQR of the upper quartile (Q3). Median (IQR) TGR0: 2.1%/month (0.2; 6.1) (lanreotide 120 mg); 2.7%/month (0.15; 6.8) (placebo). b Percentage changes in SLD during the pre-treatment period among individual patients (ITT population). Data are sorted from high percentage change in SLD to low percentage change in SLD over the pre-treatment period. A patient with a change in SLD less than 20% had PD due to the presence of new lesions. Lanreotide 120 mg, n = 100; placebo, n = 100. ITT, intention-to-treat; IQR; interquartile range; PD, progressive disease; RECIST, response evaluation criteria in solid tumors; SLD, sum of longest diameters; TGR0, pre-treatment tumor growth rate
Fig. 2
Fig. 2
Estimated TGR0 and TGRTx–Tx. *Pre-treatment TGR (TGR0) is calculated from the second imaging test during the screening period (performed 12–24 weeks after the first screening period scan). LS means and P-values are derived from a mixed model with repeated measures. CI, confidence interval; LS, least squares; TGR, tumor growth rate; TGR0, pre-treatment TGR, TGRTx–Tx, TGR between consecutive study visits during treatment
Fig. 3
Fig. 3
PFS in patients with (a) TGR0 ≤ 4%/month and (b) TGR0 > 4%/month. Analysis of PFS considers centrally assessed disease progressions (using RECIST v1.0 criteria) and any deaths reported during the study as events. A total of 14 patients in progression purely due to non-target or new lesions were excluded. TGR0 ≤ 4%, lanreotide n = 56; placebo n = 53; TGR0 > 4%, lanreotide n = 38; placebo n = 40. HRs are derived from a Cox proportional hazards model. P-values are derived from the log-rank test. CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; TGR, tumor growth rate; TGR0, pre-treatment TGR
Fig. 4
Fig. 4
Potential prognostic factors for PFS (final multivariate model). *According to RECIST v1.0. Hazard ratios [95% CI] for centrally assessed PD or death were generated from a post hoc multivariate Cox proportional hazards model. Four patients with missing TGR0 were excluded from the model. There were limited patients with progression at baseline (n = 8) and primary tumor type: hindgut n = 14. CI, confidence interval; PD, progressive disease; PFS, progression-free survival; RECIST, response evaluation criteria in solid tumors; TGR0, pre-treatment tumor growth rate
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