Treatment of Advanced Gastro-Entero-Pancreatic Neuro-Endocrine Tumors: A Systematic Review and Network Meta-Analysis of Phase III Randomized Controlled Trials

Abstract

Several new therapies have been approved to treat advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP–NENs) in the last twenty years. In this systematic review and meta-analysis, we searched MEDLINE, ISI Web of Science, and Scopus phase III randomized controlled trials (RCTs) comparing two or more therapies for unresectable GEP–NENs. Network metanalysis was used to overcome the multiarm problem. For each arm, we described the surface under the cumulative ranking (SUCRA) curves. The primary endpoints were progression-free survival and grade 3–4 of toxicity. We included nine studies involving a total of 2362 patients and 5 intervention arms: SSA alone, two IFN-α plus SSA, two Everolimus alone, one Everolimus plus SSA, one Sunitinib alone, one 177Lu-Dotatate plus SSA, and one Bevacizumab plus SSA. 177Lu-Dotatate plus SSA had the highest probability (99.6%) of being associated with the longest PFS. This approach was followed by Sunitinib use (64.5%), IFN-α plus SSA one (53.0%), SSA alone (46.6%), Bevacizumab plus SSA one (45.0%), and Everolimus ± SSA one (33.6%). The placebo administration had the lowest probability of being associated with the longest PFS (7.6%). Placebo or Bevacizumab use had the highest probability of being the safest (73.7% and 76.7%), followed by SSA alone (65.0%), IFN-α plus SSA (52.4%), 177Lu-Dotatate plus SSA (49.4%), and Sunitinib alone (28.8%). The Everolimus-based approach had the lowest probability of being the safest (3.9%). The best approaches were SSA alone or combined with 177Lu-Dotatate.

Preoperative carbohydrate loading before elective abdominal surgery: A systematic review and network meta-analysis of phase II/III randomized controlled trials

“…This problem was overcome using the NMA methodology already validated in surgical [50] and oncology literature [51]. About the primary endpoint, we observed that the differences among the different interventional approaches were minimal, and none of them was near to an ideal treatment.…”

The Antiproliferative Activity of High-Dose Somatostatin Analogs in Gastro-Entero-Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis

“…SSAs are the mainstay of treatment of well-differentiated GEP-NET since they showed antiproliferative effect [ 7 , 8 ] with a very tolerable safety profile [ 31 , 32 ]. Subsequent treatment lines at progression include PRRT, TKIs, or chemotherapy, all of which have a toxicity profile less favorable than SSAs, with PRRT preferred over other alternatives [ 33 , 34 ]. Non-conventional doses SSA (HD-SSA), achieved by either dose density or dose intensity increase, have been proposed and investigated as a potential treatment option in patients with GEP-NET whose disease progressed on standard dose SSA.…”

“…In conclusion, available literature and the results of our meta-analysis suggest that HD-SSA is not the preferred treatment choice in patients with GEP-NET who progressed on standard-dose SSA because of the short PFS and low DCR reported, especially when compared with other alternatives, such as PRRT [ 12 , 33 ]. This is markedly more evident in studies carried out in the USA, with prospective design, and in patients with metastatic disease.…”

Radiolabeled Somatostatin Analogues for Diagnosis and Treatment of Neuroendocrine Tumors

“…A recent retrospective multicenter Italian study showed that [ 177 Lu]Lu-DOTA-TATE, as well as non-conventional-dose somatostatin analogues [ 186 ], are better tolerated than chemotherapy or everolimus, with no significant difference in PFS [ 187 ]. Because a recent network meta-analysis showed that [ 177 Lu]Lu-DOTA-TATE had the highest probability of being associated with the longest PFS as compared to other approved treatments [ 188 ], it is not surprising that ongoing studies—namely, the NETTER-2 (NCT03972488) and COMPETE trials (NCT03049189)—aim at first-line positioning of PRRT. Nevertheless, shifting PRRT to earlier in the treatment algorithm for patients with NETs is associated with poorer tolerance of subsequent treatments, such as everolimus [ 189 ], or might not be associated with improved outcomes, e.g., in patients with pancreatic NETs [ 190 ].…”