Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

Abstract

Background Long‐acting somatostatin analogs (SSAs) are the primary first‐line treatment of well‐differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki‐67 ≥10% are still limited. Materials and Methods To assess the clinical outcomes of advanced, nonfunctioning, well‐differentiated panNETs with Ki‐67 ≥10% receiving first‐line long‐acting SSAs in a real‐world setting, we carried out a retrospective, multicenter study including patients treated between 2014–2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression‐free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. Results A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow‐up of 36.4 months (range, 6–173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6–16.2) and 11.9 months (95% CI, 8.6–14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2–16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1–4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8–86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2–10; p = .01). Treatment‐related adverse events were reported in 14 patients, most frequently diarrhea. Conclusion SSAs exert antiproliferative activity in panNETs with Ki‐67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. Implications for Practice The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki‐67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

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“…They did not note any statistically significant difference between octreotide and lanretotide on PFS. Lastly, they demonstrated that SSA exerted antiproliferative activity against intermediate and high grade pNETs, with both octreotide LAR and Lanreotide being associated with a median time to next treatment of 14.2 month and a median PFS of 11.9 months [ 54 ]. Although mild adverse effects, such as hyperglycemia and pancreatic enzyme insufficiency, could have been associated with SSA therapy, our patient responded very well with resolution of diarrhea, complete remission of the NME and significant metabolic improvement.…”

Finding the Appropriate Therapeutic Strategy in Patients with Neuroendocrine Tumors of the Pancreas: Guideline Recommendations Meet the Clinical Reality

“…However, there was only limited biological tumor evidence and rationale for this threshold. Interestingly, a recent study demonstrated the antiproliferative efficacy of SSA, particularly in NET G2 Ki-67 >10%, with a median PFS of 12.4 months [ 14 ].…”

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“…A subset of GEP-NET patients present with extensive tumor bulk or high proliferative rate (Ki-67 index of 10–55%). In these cases, treatment with octreotide LAR or lanreotide has questionable antiproliferative effects [ 71 ]. Given its ORR of 39%, which increases to 55% in panNETs [ 29 ], 177 Lu-DOTATATE can be considered as first-line therapy if response is clinically necessitated [ 72 ].…”