1. The median overall survival for patients receiving177Lu-Dotatate and intramuscular, long-acting octreotide was 47.0 months and 36.3 months respectively
2. Few patients receiving 77Lu-Dotatate and intramuscular octreotide experienced grade 3 or worse adverse events such as myelodysplastic syndrome, nephrotoxicity and refractory cytopenia with multilineage dysplasia.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Gastroentero-pancreatic neuroendocrine tumours (GEP-NETs) are rare tumours that can be formed anywhere along the gastrointestinal tract. Midgut NETs are the most common subtype of advanced, well-differentiated GEP-NETs. The current standard of care to treat metastatic, low, or intermediate grade GEP-NETs are somatostatin analogues (e.g. octreotide). Recently, the use of radiolabeled somatostatin analogues, peptide receptor radionuclide therapy (PRRT), has been explored as potential targeted treatment of GEP-NETs. Therefore, this study aimed to evaluate the efficacy and safety of 177Lu-Dotatate in patients with advanced, well-differentiated, progressive midgut NETs. Patients were divided into two groups: 177Lu-Dotatate and intramuscular (IM) octreotide and the other receiving high‑dose, IM octreotide. The 5-year overall survival (OS) was 37.1% in the treatment group and 35.4% in the control group. The final overall survival in between the two study groups did not differ significantly. The median overall survival in the treatment group was 47.0 months and 36.3 months. 6% of the patients in the combined treatment group had grade 3 or worse treatment-related serious adverse events (AE), with no new safety signals reported since the last safety analysis cutoff. These serious adverse events include myelodysplastic syndrome, nephrotoxicity and refractory cytopenia with multilineage dysplasia. Limitations to the study include potential confounding factors when calculating the overall HR. 36% of the control group received PPRT (e.g.177Lu-Dotatate) as their subsequent anticancer therapy during long-term follow-up. Even though the overall HR was adjusted for this factor, there may be other confounding factors that may not be accounted for (e.g. subsequent anti-cancer therapy received by the treatment group). Overall, this study demonstrated that 177Lu-Dotatate plus octreotide did not show a significant improvement in the OS compared to the high octreotide group. Further investigation may be needed to better understand the efficacy and safety of PRRT in heavily metastasized NETs and the impact of the tumor load.
In-Depth [randomized controlled trial]: This was an open-label, intention-to-treat, phase III randomized trial of 231 patients at 41 institutes across Europe and the United States. Patients were eligible if they had locally advanced or metastatic, well-differentiated, somatostatin receptor-positive midgut NETs, 60 Karnofsy performance status score, and were taking fixed-dose long-acting octreotide. The treatment group received 4 cycles of intravenous 177Lu-Dotatate and intramuscular, long-acting octreotide 30mg with each cycle, every 8 weeks according to the study protocol which included up to 18 months of treatment, and then switched to the control group regimen after PRRT completion. The control group received high‑dose, intramuscular, long-acting, octreotide 60 mg every 4 weeks. If symptom control was needed throughout the study, patients received short-acting octreotide. Once the treatment was completed or discontinued, patients were followed-up to monitor for safety. During this time, patients could receive additional anticancer treatment based on their physician’s recommendations. The median follow-up period was 76.3 months (range: 0.4-95.0 months) in the treatment group and 76.5 months (range: 0.1-92.3 months) in the control group. The final overall survival in between the two study groups did not differ significantly (Hazards Ratio (HR): 0.84, 95% CI: 0.60-1.17). The median overall survival in the treatment group was 47.0 months (95% CI: 0.60-1.17) and 36.3 months (95% CI: 25.9-51.7 months).
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