Abstract
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Objectives: Alpha therapy is considered better than beta-emitting 177LuCl3 due to the double-stranded DNA breaks causing high cytotoxic activity on the cellular level and minimal bystander effects. On the literature search, only one pre-clinical study by Miederer et al. reported the efficacy of 225Ac-DOTATOC in the nude mice models of NETs and proved 225Ac to enhance the efficacy of PRRT. The objective of this study was to investigate and present the early results on the safety and efficacy of 225Ac-DOTATATE targeted alpha therapy (TAT) in patients with advanced, progressive, 177Lu-DOTATATE refractory, somatostatin receptor (SSTR) positive, metastatic gastroenteropancreatic neuroendocrine tumors (GEP NETs).
Methods: This study was approved by the Institute Ethics Committee (IEC No:517/2018). We recruited 22 patients (male: 9; female:13; mean age, 55.3±6.3years range: 46-72 years) and all patients except 2 demonstrated morphological disease progression on 177Lu-DOTATATE therapy. Patients underwent a screening 68Ga-DOTANOC PET/CT scan to assure high SSTR expression and progressive disease to prior therapies. Systemic TAT was performed in all the patients with 225Ac-DOTATATE (100KBq/Kg body weight) at an interval of 8 weeks up to 3 cycles. The patients were treated between April 2018 to December 2018 with a median follow-up duration of 7 months (range: 4 - 9 months). Hematologic, kidney, and liver function tests were repeated before and after every cycle of 225Ac-DOTATATE TAT at 2, 4 and 8-week intervals. Treatment-related side effects were assessed every 2 weeks on the basis of physical examination, vital signs, laboratory results (hematologic, kidney and liver function levels) and adverse events graded according to the CTCAE v5.0. Efficacy assessment included morphological and molecular tumor responses measured by diagnostic contrast-enhanced 68Ga-DOTANOC PET/CT scans according to RECIST 1.1 and PERCIST 1 criteria, respectively.
Results: The most common adverse effects (AEs) were nausea (72%), vomiting (72%), gastritis (68%), and appetite loss (86.3%), but were limited to grade 1 or 2. Majority of the patients experienced these AEs at the time of amino acid infusion which was administered during 225Ac-DOTATATE therapy and was resolved after few hours of amino acid infusion. All the other AEs such as fatigue or asthenia, diarrhoea, appetite loss, abdominal pain, abdominal distension, weight loss, peripheral edema, headache, dizziness, and flushing were also identified which were limited to grade 1 or 2, except for 1 patient with grade 3 abdominal distension and fatigue. None of the patients experienced grade 3 or 4 hematotoxicity, renal insufficiencies or hepatotoxicity. In a median follow-up duration of 7 months, morphological response assessment was assessed in 17 patients which revealed partial remission in 9, Stable disease in 7, and Progressive disease in 1 patient. Similarly, molecular tumor response evaluation in 17 patients revealed partial remission in 14, stable disease in 2, and disease progression in 1 patient. There were no treatment related deaths. Currently, therapy is discontinued for only one patient with disease progression.
Conclusions: Our initial results indicate 225Ac-DOTATATE TAT safe with low and transient side-effects. Clinical evidence demonstrates objective molecular tumor response 82% of patients, respectively. Clinically significant grade 3 adverse event occurred only in one patient. This study is an ongoing trial and we have presented only the preliminary results. We are recruiting more number of patients and maintaining the follow-up. Further results on overall survival and progression-free survival will be derived after a longer follow-up duration.