Predictors of antiproliferative effect of lanreotide autogel in advanced gastroenteropancreatic neuroendocrine neoplasms

Abstract

Purpose The antiproliferative properties of lanreotide autogel (LAN) in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) were demonstrated in the CLARINET study. However, there is limited literature regarding factors that affect progression-free survival (PFS) in patients with GEP NENs treated with LAN. Methods We identified a total of 191 treatment-naive patients with advanced GEP NENs and positive SSTR uptake on imaging (Octreoscan or 68 Gallium DOTATATE Positron Emission Tomography [ 68 GaPET]) who received first-line LAN monotherapy, albeit at various starting doses (60, 90 or 120 mg/month). A group of 102 patients who initiated treatment at the standard dose of 120 mg/month were included in the study and further evaluated by univariate and multivariate analyses to identify predictors of PFS. Results The location of tumour primary was in the small bowel in 63 (62%), pancreas in 31 (30%) and colon/rectum in 8 patients (8%). The tumours were well-differentiated, and the majority were grade 1 (52%), or 2 (38%). About 60% of cases had progressive disease at the time of treatment initiation. Most patients with available pretreatment nuclear medicine imaging (Octreoscan or 68 Ga PET) had a Krenning score of 3 (44%) or 4 (50%). The median PFS for the entire cohort was 19 months (95% CI 12, 26 months). The univariate analysis demonstrated that grade 2 tumours, progressive disease at baseline and metastatic liver disease were associated with a significantly shorter PFS, while other evaluated variables did not affect PFS at a statistically significant level. However, at multivariate analysis only the tumour grade remained statistically significant. Conclusions The current study showed that, of many evaluated variables, only the tumour grade was predictive of PFS duration and this should be considered during patient selection for treatment.

The State-of-the-Art Mechanisms and Antitumor Effects of Somatostatin in Colorectal Cancer: A Review

“…The antiproliferative and pro-apoptotic activities of somatostatin analogues (SSAs) are mainly used in the treatment of highly differentiated GEP-NENs and other tumors that express SSTRs [ 22 , 46 , 183 , 254 , 255 , 256 , 257 ]. However, treatment in SSTR-negative NETs are also presented [ 254 ].…”

Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies

“…An increased tumor grade [ 42 , 172 , 179 , 223 ], presence of a poorly-differentiated tumor [ 175 ] and an increasing Ki-67 index [ 173 ] are reported to correlate with worse outcomes with SSA treatment ( Table 2 , Right Panel). Some studies reported that a Ki-67 threshold of 5% was more predictive of PFS with SSA treatment than the cut-off value proposed by 2010 WHO classification to separate G1 and G2 (i.e., <3%) [ 172 , 224 ].…”

“…Some studies reported that a Ki-67 threshold of 5% was more predictive of PFS with SSA treatment than the cut-off value proposed by 2010 WHO classification to separate G1 and G2 (i.e., <3%) [ 172 , 224 ]. SSA therapy is less effective in patients with bone and peritoneal metastases [ 173 ], as well as with any liver metastases [ 42 ] or a high hepatic tumor load [ 173 , 174 , 177 , 179 , 225 ], suggesting its limited role in advanced panNEN patients with aggressive tumors.…”

“…Recently, two additional Phase 3 studies have shown the anti-tumor effectiveness of another multityrosine kinase receptor inhibitor, surufatinib [ 33 ] in both advanced panNENs [ 34 ] and extrapancreatic NENs (carcinoids) [ 35 ]. PanNENs ectopically overexpress somatostatin receptors type 1–5 (SSTR 1–5) and numerous studies showed their activation has anti-tumor and anti-secretory effects in NENs [ 22 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Like recent studies demonstrating that the somatostatin analogue (SSA) octreotide had an anti-tumor effect extending PFS in ileal carcinoids and other tumors [ 22 , 37 , 38 , 40 , 45 ], the long acting SSA lanreotide demonstrated similar anti-tumor activity in a recent Phase 3 trial involving patients with advanced gastroenteropancreatic NENs (GEP-NENs), in addition to its having an anti-secretory effect [ 22 , 37 , 46 ].…”

“…PanNENs as well as NENs in other locations and many more common neoplasms frequently ectopically overexpress various G-protein coupled receptors, and these are increasingly being used to not only localized these tumors using various receptor ligands, as well as for targeted delivery of cytotoxic compounds [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. The overexpression of somatostatin receptors by panNENs and other NENs is also being used to treat advanced disease using radiolabeled somatostatin analogues [ 25 , 40 , 42 , 54 , 55 , 56 , 57 ]. The efficacy of peptide receptor radionuclide therapy (PRRT) using 177 Lutetium (Lu) -DOTATATE was also reported from another Phase 3 trial involving patients with advanced midgut NENs [ 58 ] and from studies of patients with advanced panNENs primarily from Rotterdam [ 59 ].…”