Well-differentiated neuroendocrine tumors (NETs) are a group of heterogeneous rare tumors. They are often slow-growing and patients can have very long survival, even at the metastatic stage. The evaluation of tumor progression and therapeutic responses is currently based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST) criteria. As for other malignancies, RECIST criteria are being reexamined for NETs in the era of targeted therapies because tumor response to targeted therapies is rarely associated with shrinkage, as opposed to prolonged progression-free survival. Therefore, size-based criteria no longer seem to be suitable to the assessment of NET progression and therapeutic responses, especially considering targeted therapies. New imaging criteria, combining morphological and functional techniques, have proven relevant for other malignancies treated with targeted therapies. To date, such studies have rarely been conducted on NETs. Moreover, optimizing the management of NET patients also requires considering clinical, biological, and pathological aspects of tumor evolution. Our objectives herein were to comprehensively review current knowledge on the assessment of tumor progression and early prediction of therapeutic responses and to broaden the outlook on well-differentiated NETs, in the era of targeted therapies.
Louis de Mestier, Clarisse Dromain, Gaspard d'Assignies, Jean-Yves Scoazec, Nathalie Lassau, Rachida Lebtahi, Hedia Brixi, Emmanuel Mitry, Rosine Guimbaud, Frédéric Courbon, Michèle d'Herbomez and Guillaume Cadiot
Laetitia Dahan, Frank Bonnetain, Philippe Rougier, Jean-Luc Raoul, Eric Gamelin, Pierre-Luc Etienne, Guillaume Cadiot, Emmanuel Mitry, Denis Smith, Frédérique Cvitkovic, Bruno Coudert, Floriane Ricard, Laurent Bedenne, Jean-François Seitz and for the Fédération Francophone de Cancérologie Digestive (FFCD) and the Digestive Tumors Group of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC)
The aim of this randomized multicenter phase III trial was to compare chemotherapy and interferon (IFN) in patients with metastatic carcinoid tumors. Patients with documented progressive, unresectable, metastatic carcinoid tumors were randomized between 5-fluorouracil plus streptozotocin (day 1–5) and recombinant IFN-α-2a (3 MU×3 per week). Primary endpoint was progression-free survival (PFS). From February 1998 to June 2004, 64 patients were included. The two arms were well matched for median age, sex ratio, PS 0–1, previous chemotherapy, surgery, or radiotherapy. The median PFS for chemotherapy was 5.5 months versus 14.1 for IFN (hazard ratio=0.75 (0.41–1.36)). Overall survival (OS), tolerance, and effects on carcinoid symptoms were not significantly different. Despite a trend in favor of IFN, there was no difference in PFS and OS in advanced metastatic carcinoid tumors and therapeutic effect of both treatments was mild.
Martyn E Caplin, Marianne Pavel, Jarosław B Ćwikła, Alexandria T Phan, Markus Raderer, Eva Sedláčková, Guillaume Cadiot, Edward M Wolin, Jaume Capdevila, Lucy Wall, Guido Rindi, Alison Langley, Séverine Martinez, Edda Gomez-Panzani, Philippe Ruszniewski and on behalf of the CLARINET Investigators
In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.