Meta-Analysis of Randomized Clinical Trials Comparing Active Treatment with Placebo in Metastatic Neuroendocrine Tumors

Abstract

Background. Most guidelines still recommend active surveillance for patients with asymptomatic, unresectable neuroendocrine tumors (NETs). However, recent findings from several randomized placebo-controlled trials suggest that most patients would benefit from active treatment. We conducted a metaanalysis of pooled outcomes from clinical trials in which an active treatment arm was compared with placebo to determine whether active treatment provides a survival advantage. Materials and Methods. This meta-analysis evaluated six trials that compared a medication with placebo in patients with an asymptomatic, metastatic NET. The trials were heterogenous with regard to the active medication (octreotide, lanreotide, sunitinib, everolimus, Lu-Dotatate) and tumor localizations (gastrointestinal, pancreas, lung). Overall survival (OS) and progression-free survival (PFS) for the placebo and active treatment arms were obtained from individual trial data and combined to obtain pooled outcomes. Results. The individual trials all reported significantly better PFS outcomes for active treatment. The pooled data confirmed this advantage. At months 3, 6, 12, 18, and 24, pooled PFS rates for the placebo and treatment arms, respectively, were 92.9% versus 96.9%; 54.3% versus 83.7%; 35.5% versus 68.5%; 25.1% versus 54.7%; and 17.7% versus 61.0%. OS was also higher in the active treatment groups. At months 6, 12, 24, 36, 48, and 60, OS rates (placebo vs. active treatment), respectively, were 88.1% versus 93.4%; 84.1% versus 86.2%; 67.4% versus 76%; 56.6% versus 64.4%; 49.9% versus 61.0%; and 41.7% versus 45.9%. Conclusion. This meta-analysis confirms findings from recent clinical trials indicating that active treatment yields better survival outcomes than placebo. Importantly, these findings were obtained across a wide range of patient profiles and diverse medical treatments for metastatic NETs. Given the lack of reliable prognostic factors to determine a priori which patients are unlikely to benefit from active treatment, these findings support early treatment in most patients. The Oncologist 2019;24:e1315-e1320 Implications for Practice: Although most guidelines still recommend active surveillance for patients diagnosed with metastatic neuroendocrine tumors, the results of this meta-analysis, together with recent data from key clinical trials, suggest that most patients could benefit from upfront active treatment. However, more data are needed to confirm this.

Rare Malignant Indications for Liver Transplantation: A Collaborative Transplant Study Report

“…This challenges the exceptional status of metastasizing NET as the only indication for LT in secondary hepatic malignancy. If the outcome of LT for metastasizing NET for the majority of potential recipients is closer to the results reported herein than to the results from one of the few specialized high-volume centers, the option to remain on a palliative chemotherapy course could be a viable alternative for some patients, as it offers comparable long-term patient survival (60-month patient survival after LT in CTS: 55.7 vs. 45.9% and median patient survival of up to 84.7 months with palliative treatment) ( 36 , 37 ).…”

Peptide Receptor Radionuclide Therapy with [177Lu]Lu-DOTA-TATE in Patients with Advanced GEP NENS: Present and Future Directions

“…As above mentioned, treatment with [ 177 Lu]Lu-DOTA-TATE is placed as a secondline therapy along with everolimus in midgut NET tumors and as third or fourth line in pancreatic tumors. Despite the lack of data from specific phase III clinical trials, there is positive evidence of efficacy and safety in advanced pancreatic NET patients in which PRRT could surpass on treatment sequencing other targeted therapies [61,62]. Moreover, a potential increasing toxicity used after prior chemotherapy or targeted therapy has been described, which might justify an earlier use of PRRT in selected patients [36].…”

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

“…Recent meta-analyses/reviews including previous randomized control trials [ 61 , 102 , 103 ] of treatments of patients with advanced panNENs/carcinoids, as well as a nationwide population study in the Netherlands [ 104 ], suggest a higher survival benefit with PRRT treatment than the other systemic therapies in these patients. A second recent meta-analysis [ 105 ] compared active surveillance, which is recommended for patients initially diagnosed with metastatic NENs in several guidelines, to active antitumor treatment (somatostatin analogues, sunitinib, everolimus, PRRT), and found that active treatment extended to both PFS and OS. Another recent meta-analysis comparing the cytoreductive effect between different therapeutic agents reports chemotherapy alone (capecitabine/temozolomide) or in combination showed the strongest effect of cytoreduction in patients with advanced panNENs, followed by PRRT and sunitinib [ 106 ].…”