Radiolabelled somatostatin analogue treatment in gastroenteropancreatic neuroendocrine tumours: factors associated with response and suggestions for therapeutic sequence
Davide CampanaGabriele CapursoStefano PartelliFrancesca NoriFrancesco PanzutoDomenico TamburrinoGiulia CacciariGianfranco Delle FaveMassimo FalconiPaola Tomassetti
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Radionuclide therapy
Progression-free survival
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Abstract: Peptide receptor radionuclide therapy (PRRT), developed over the last two decades, is carried out using radiopharmaceuticals such as 90Y-DOTA-Tyr3-octreotide and 177Lu-DOTA-Tyr3-octreotate (177Lu-Dotatate). These radiocompounds are obtained by labeling a synthetic somatostatin analog with a β-emitting radioisotope. The compounds differ from each other in terms of their energetic features (due to the radionuclide) and peptide receptor affinity (due to the analog) but share the common characteristic of binding specific membrane somatostatin receptors that are (generally) overexpressed in neuroendocrine neoplasms (NENs) and their metastases. NENs are tumors arising from diffuse neuroendocrine system cells that are classified according to grading based on Ki67 percentage values (Grades 1 and 2 are classed as neuroendocrine tumors [NETs]) and to the anatomical site of occurrence (in this paper, we only deal with gastroenteropancreatic [GEP]-NETs, which account for 60%–70% of all NENs). They are also characterized by specific symptoms such as diarrhea and flushing (30% of cases). Despite substantial experience gained in the area of PRRT and its demonstrable effects in terms of efficacy, safety, and improvement in quality of life, these compounds are still not registered (registration of 177Lu-Dotatate for the treatment of midgut NETs is expected soon). Thus, PRRT can only be used in experimental protocols. We provide an overview of the work of leading groups with wide-ranging experience and continuity in data publication in the area of GEP-NET PRRT and report our own personal experience of using different dosage schedules based on the presence of kidney and bone marrow risk factors. Our results on the retreatment of patients previously administered 90Y-DOTA-Tyr3-octreotide with a low dosage of 177Lu-Dotatate are also included. A comment on potential future developments of PRRT in GEP-NETs is provided. Keywords: 90Y-Dotatoc, 177Lu-Dotatate, radiopharmaceutical, radiolabelled receptors, neuroendocrine malignancies, delivered activity
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Radionuclide therapy for neuroendocrine tumors is a form of systemic radiotherapy that allows the administration of targeted radionuclides into tumor cells that express a large quantity of somatostatin receptors. The two most commonly used radio-peptides for radionuclide therapy in neuroendocrine tumors are 90Y-DOTATOC and 177Lu-DOTATATE. Radio-peptides have been used for several years in the treatment of advanced neuroendocrine tumors. Recently, the randomized Phase III study NETTER-1 compared177Lu-DOTATATE versus high-dose (double-dose) octreotide LAR in patients with metastatic midgut neuroendocrine tumors, and demonstrated its efficacy in this setting. Strong signals in favor of efficiency seem to exist for other tumors, in particular for pancreatic and pulmonary neuroendocrine tumors. This focus on radionuclide therapy in gastroenteropancreatic and pulmonary neuroendocrine tumors addresses the treatment modalities, the validated and potential indications, and the safety of the therapy.
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The intent of this study was to evaluate the safety and efficacy of high-activity 111In-pentetreotide in patients with neuroendocrine tumors. Thirty-two patients with pentetreotide-avid neuroendocrine tumors received therapy from August 2005 to November 2006. Fourteen (14) patients received 1 treatment and 18 patients received 2 treatments. Patients were followed an average of 12.73 months (range 1.2–24.5). Seventeen (17) patients (53%) had grade I or II hematologic toxicities, and 1 patient had grade III thrombocytopenia. One patient had grade II liver toxicity, which appeared 4 weeks after therapy and resolved on week 5. No patient had renal toxicity. Of the patients who completed 2 treatment cycles, 2 of 18 patients had partial disease regression, and 16 of 18 patients with previously progressive disseminated neuroendocrine disease achieved stable disease by imaging criteria. A decrease in serum tumor markers was observed in 14 of 18 patients given 2 therapies. A clinical response was achieved in 84% of the patients. Upon interim analysis, median survival was approximately 13 months (range 1.2–24.5). These results show that high-activity 111In-pentetreotide therapy is effective in patients with progressive disseminated neuroendocrine tumors.
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Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-[DOTA0,Tyr3]-octreotate (177Lu-DOTATATE) has become an established second- or third-line treatment option for patients with somatostatin receptor (SSTR)-positive advanced well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Clinical evidence of the efficacy of PRRT in tumor control has been proven and lower risks of disease progression or death are seen combined with an improved quality of life. When appropriate patient selection is performed, PRRT is accompanied by limited risks for renal and hematological toxicities. Treatment of NET patients with PRRT requires dedicated clinical expertise due to the biological characteristics of PRRT and specific characteristics of NET patients. This review provides an overview for clinicians dealing with NET on the history, molecular characteristics, efficacy, toxicity and relevant clinical specifics of PRRT.
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177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is now approved for patients with advanced gastroenteropancreatic neuroendocrine tumors (NET), and it is therefore important to understand the efficacy and safety of PRRT in this patient population. PRRT efficacy and safety outcomes have frequently been summarized for patient populations with gastroenteropancreatic NET, but not specifically in patients with pancreatic NET (panNET). The pivotal phase 3 trial of 177Lu-DOTATATE PRRT in NET was restricted to patients with a midgut primary site. No phase 3 trial data on PRRT treatment outcomes are currently available for the panNET patient population. This review presents the available evidence for panNET treatment outcomes with PRRT and demonstrates that the available data favor PRRT as a modality for this NET primary site. However, several other therapies for advanced panNET are currently available, and the sequencing and combination of PRRT with these other therapies is set to become the big challenge for the future of panNET management. Patient, tumor, and logistical factors (tumor burden, expression of somatostatin receptors, availability of PRRT, patient preferences, and concerns over long-term toxicity) need to be taken into consideration when selecting therapy.
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Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common form of neuroendocrine neoplasia, but there is no current consensus for the sequencing of approved therapies, particularly with respect to peptide receptor radionuclide therapy (PRRT). This comprehensive review evaluates the data supporting approved therapies for GEP-NETs and recommendations for therapeutic sequencing with a focus on how PRRT currently fits within sequencing algorithms. The current recommendations for PRRT sequencing restrict its use to metastatic, inoperable, progressive midgut NETs; however, this may change with emerging data to suggest that PRRT might be beneficial as neoadjuvant therapy for inoperable tumors, is more tolerable than other treatment modalities following first-line standard dose somatostatin analogs, and can be used as salvage therapy after disease relapse following prior successful cycles of PRRT. PRRT has also been shown to reduce tumor burden, improve quality of life, and prolong the time to disease progression in a broad spectrum of patients with GEP-NETs. As the various potential benefits of PRRT in GEP-NET therapy continues to expand, it is necessary to review and critically evaluate our treatment algorithms for GEP-NETs.
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Abstract: Peptide receptor radionuclide therapy (PRRT) is a paradigm shifting approach to the treatment of neuroendocrine tumors. Although there are no prospective randomized trials directly studying PRRT in pancreatic neuroendocrine tumors (panNETs), there are data to suggest benefit in this patient population. Collectively, the data, consisting of two prospective and six retrospective studies, show a median PFS ranging from 20 to 39 months and a median OS ranging from 37 to 79 months. There are ongoing (and upcoming) prospective, randomized trials of PRRT in panNETs, which will provide further evidence to support this approach. Keywords: pancreatic neuroendocrine tumor, panNET, peptide receptor radionuclide therapy, PRRT, theranostics
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1438 Objectives: Neuroendocrine tumors (NET) are a heterogenous group of tumors, once thought rare, but now show a rising incidence. The tumor often times is indolent, thus leading to a late diagnosis at an advanced metastatic stage. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogue has emerged as a new encouraging systemic treatment modality, especially for unresectable metastasized NETs. PRRT is not only known to reduce tumor burden but also NET-related symptoms, thus increasing quality of life. We present here our initial experience with lutetium-177 (177Lu) labeled Dotatate since FDA approval in January 2018 in patients with NET and other somatostatin receptor (SSTR) positive tumors.
Methods: Sixty-three patients (33 males and 30 females; 37 - 81-year-old, mean ± SD: 62.1 ± 10.4 years) were treated with PRRT at our institution. Thereof 58 had progressing NETs (32 of the pancreas, 18 of the small intestine, 1 of the coecum, 1 of the appendix, 1 of the stomach and 5 of unknown primary), 3 had a paraganglioma, and 2 had a pheochromocytoma. Treatment was scheduled every 8 weeks for a total of 4 cycles. 68Ga-Dotatate PET/CT was performed at baseline, interim after 2 cycles, and following completion of PRRT. RECIST and SSTR density based on change of SUVmax were used to evaluate response to therapy. We assessed progression-free survival (PFS), objective response rate (ORR) and, considering the short follow-up time, an interim overall survival (OS).
Results: 36/63 (57.1%) patients completed all 4 cycles of PRRT, receiving a full dose of 7400MBq each. 10/63 (15.9%) patients had to discontinue treatment (4 after 1st cycle, 3 after 2nd cycle, and 3 after 3rd cycle) due to co-morbidities. 17/63 (27%) patients are still scheduled to receive additional cycles. The 11-month PFS rate was 57% and the 14-month PFS rate was 62%. The ORR was 26%. In the interim OS analysis, 8 deaths occurred from co-morbidities.
Conclusions: In our heterogenous and heavily pretreated patient cohort, the preliminary data show overall good results of PRRT with a high ORR.
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Bronchopulmonary (BP) neuroendocrine tumors (NETs) comprise a spectrum of tumors that develop from respiratory neuroendocrine cells and represent ~20% of all lung neoplasia and ~30% of all NETs. The only curative treatment is surgical resection. For well-differentiated forms (typical and atypical carcinoids), medical therapy ranges from bioactive agents (e.g., somatostatin analogs), to biotherapy (e.g., everolimus), standard chemotherapy and peptide receptor radionuclide therapy (PRRT). PRRT with radiolabeled somatostatin analogs is an innovative treatment for inoperable or metastasized, well/moderately differentiated, NET. Initially developed for gastroenteropancreatic tumors, it is also used in BP-NET because these tumors express the target receptor. Two decades of clinical trials with either 90Y-octreotide or 177Lu-octreotate, have demonstrated the efficacy of PRRT, as measured by tumor response, symptom relief and quality of life (QoL) improvement. PRRT with 90Y- and 177Lu-peptides is generally well-tolerated and adverse events (kidney and bone marrow) are modest. The paper illustrates the history, technique and results of this treatment in the few dedicated studies and the many BP NET cases embedded within larger NET series. The limitations of the present body of information are addressed, and the future perspectives, in terms of prospective studies required to define the position of PRRT in the therapeutic algorithm of BP-NETs and the need for predictive molecular biomarkers to guide future studies, are discussed.
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