Repeat Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors: A NET Center of Excellence Experience

Repeat Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors: A NET Center of Excellence Experience | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Repeat Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors: A NET Center of Excellence Experience Udhayvir S Grewal, Bradley T Loeffler, Alexander Paschke, Joseph S. Dillon, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4009283/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Introduction: The available data for the safety and efficacy of repeat Peptide Receptor Radionuclide Therapy (PRRT) are almost exclusively from European centers. We present an updated experience with repeat PRRT in a cohort of US patients with neuroendocrine tumors (NETs) at our NET center of excellence. Methods We used our single-center longitudinal NET registry to identify patients who had been previously treated with at least one dose of PRRT (PRRT 1, either 177 Lu DOTATATE or 90 Y DOTATOC) and following radiographic disease progression (per RECIST 1.1 criteria) were re-treated with a second course of PRRT (PRRT 2). We reviewed patient, tumor and treatment characteristics, objective response rates and toxicities after PRRT 1 and PRRT 2. Results A total of 11 patients were included in the analysis. 45.5% (5/11) patients received 177 Lu DOTATATE PRRT only, both for PRRT1 and PRRT 2, while 54.5% (6/11) patients received 90 Y DOTATOC PRRT for PRRT1. At first restaging scan after PRRT2 (3–6 months), 18.2% (2/11), 36.4% (4/11) and 27.3% (3/11) patients had PR, SD and PD respectively; 2/11 patients (18.2%) died before first restaging scan. Median PFS for PRRT1 (n = 11) was 25.4 months and median PFS (n = 10) for PRRT2 was 13.1 months (p = 0.0001). We did not find a statistically significant difference between the occurrence of short and long-term hematological toxicities as well as renal toxicity after PRRT1 and PRRT2. Conclusion We show that repeat PRRT may benefit select patients and has an acceptable safety profile. In our cohort, PFS was significantly lower after PRRT2 as compared to PRRT1. Figures Figure 1 Figure 2 Figure 3 Background Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies which are classified according to their site of origin and pathological characteristics such as grade and differentiation. Well-differentiated NENs are referred to as neuroendocrine tumors (NETs), which are further sub-classified based on their Ki-67 proliferation index into grade 1(Ki-67 1–2%), grade 2 (Ki-67 3–20%) and grade 3 (Ki-67 > 20%) NETs. Poorly differentiated NETs are referred to as neuroendocrine carcinomas (NECs) [ 1 ]. Peptide receptor radionuclide therapy (PRRT) targets somatostatin receptor (SSTR) using somatostatin analogs (SSAs) that are labeled with radioactive isotopes. Yttrium-90 ( 90 Y) was previously used as a radiolabeling agent but was eventually replaced by Lutetium-177 ( 177 Lu) as the latter is associated with reduced renal toxicity. 177 Lu-DOTATATE (Lutathera®) with octreotide long-acting release (LAR) 30 mg was shown to be associated with superior progression free survival (PFS) and quality of life in the phase III NETTER-1 study, compared to high dose octreotide LAR (60 mg once every 4 weeks) among patients with small bowel NETs; median PFS not reached in the PRRT arm compared to 8.4 months in the octreotide LAR alone arm (HR = 0.21 95% CI 0.13 to 0.33, p < 0.001). A trend towards improved overall survival was also noted but this was not statistically significant (p = 0.30) [ 2 ] [ 3 ]. Although the NETTER-1 study included only subjects with small bowel NETs, the US Food and Drug Administration (USFDA) approved the therapy for pancreatic NETs as well, based on prospective data from European centers [ 4 ]. PRRT is endorsed as a potential therapeutic option for gastroenteropancreatic NETs, bronchial NETs and other rarer NETs such as paraganglioma or pheochromocytomas by the National Comprehensive Cancer Network (NCCN) [ 5 ]. Various societies have recommendations in place regarding sequencing of PRRT with respect to other standard of care treatment options in patients with advanced NETs [ 6 ], [ 7 ], [ 8 ]. However, due to a lack of robust prospective data regarding safety and feasibility, there is no direct guidance on the use of repeat (or salvage) PRRT in patients with NETs. The USFDA approval for 177 Lu DOTATATE PRRT came through in 2018, however this treatment modality has been widely available in European nations since early 2000s. Therefore, the data for the safety and efficacy of repeat PRRT are almost exclusively from European centers. We present an updated experience with repeat PRRT in a cohort of US patients at our NET center of excellence. Methods We used our single-center longitudinal neuroendocrine tumor (NET) registry to identify patients who had been previously treated with at least one dose of PRRT (PRRT 1, either 177 Lu DOTATATE or 90 Y DOTATOC) and following radiographic disease progression (per RECIST 1.1 criteria) were re-treated with a second course of PRRT (PRRT 2). Study schema is highlighted in Fig. 1 . We included patients with histological confirmation of grade 1 or grade 2 NET and metastatic disease, age > 18 years, and performance status of ECOG 2 or better. Only patients with radiotracer avid disease on 68 Ga- DOTATATE scan were included. Patients with poorly differentiated NEC or those who received alpha particle emitting PRRT were not included. All patients had evidence of acceptable hematological parameters and preserved liver and renal function prior to both PRRT1 and PRRT2. Per our institutional protocol, PRRT is offered only in patients with hemoglobin > 8 gm/dL, platelet count > 75,000 per cu. mm or estimated glomerular filtration rate > 45 ml/min. All patients with functional syndromes continued SSAs between and after PRRT. We reviewed patient, tumor and treatment characteristics, objective response and toxicities after PRRT 1 and PRRT 2. The United States National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 was used for grading of toxicities. The study was conducted in accordance with the Declaration of Helsinki. All patients in the database provided informed consent in accordance with the protocol approved by the Institutional Review Board of the University of Iowa Holden Comprehensive Cancer Center (Iowa City). Fisher’s exact test was used to evaluate differences in the rate of toxicity between PRRT1 and PRRT2. Stratified Cox regression via the PWP Gap Time model for recurrent events proposed by Prentice, Williams, and Peterson was used to estimate the effect of disease characteristics on progression-free survival (PFS) after repeat PRRT [ 9 ]. For assessing the progression free survival, time was computed from the start of PRRT to the date of progression or death due to any cause, or the date last known to be progression-free in the absence of progression. Survival probabilities were plotted along with 95% confidence intervals. Estimated effects were reported as hazard ratios (HR) along with 95% confidence intervals. All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Results From June 2018 to July 2023, a total of 153 patients received at least 1 dose of 177 Lu DOTATATE PRRT at our institution post FDA approval, out of which, 13/153 (8.5%) patients received repeat PRRT. We excluded 2/13 patients due to lack of adequate follow up and included a total of 11 patients for the final analysis. Patient characteristics Baseline characteristics of the included patients are listed in Table 1 . All patients included were White (11/11, 100%). Mean age of the participants was 65.9 ± 8.2 years and 54.5% (6/11) patients were males. Most patients had grade 2 (9/11, 81.8%) followed by grade 1 NET (2/11, 18.2%) and all except one patient included had gastroenteropancreatic origin NETs (10/11, 90.9%). Table 1 Baseline characteristics of patients included in the final analysis [F: female, M: male, W: white, NF: non-functional]. Variable Level N = 11 Sex F 5 (45.5) M 6 (54.5) Race W 11 (100.0) Primary Site Pancreas 6 (54.5) Small Bowel 4 (36.4) Unclear Origin 1 (9.1) Functional Functional 7 (63.6) NF 4 (36.4) Grade 1 2 (18.2) 2 9 (81.8) Number of Prior Therapies 1 1 (9.1) 2 5 (45.5) 3 1 (9.1) 4 1 (9.1) 5 2 (18.2) 6 1 (9.1) Treatment characteristics 45.5% (5/11) patients received 177 Lu DOTATATE PRRT only, both for PRRT1 and PRRT 2, while 54.5% (6/11) patients received 90 Y DOTATOC PRRT for PRRT1. Median number of lines therapies before PRRT1 and between PRRT1 and PRRT2 were 2 (IQR 2,5) and 1 (IQR 1,2) respectively. Median time duration between PRRT1 and PRRT2 was 36.1 months. Patients received a median of 3 (IQR 2, 4) and 3 (IQR 1,4) cycles for PRRT1 and PRRT2 respectively. Median radioactive dose with PRRT1 and PRRT2 was 176 mCi and 196 mCi respectively. Table 2 highlights treatment characteristics for the patients included in the analysis. Table 2. Treatment characteristics and outcomes for patients included in the analysis. [PRRT: peptide receptor radionuclide therapy, PD: progressive disease, PR: partial response, SD: stable disease]. Variable Level N = 11 Type (PRRT1) 177 Lu 5 (45.5) 90 Y 6 (54.5) Number of Cycles (PRRT1) 1 1 (9.1) 2 1 (9.1) 3 6 (54.5) 4 3 (27.3) Restaging (PRRT1) PD 1 (9.1) PR 5 (45.5) SD 5 (45.5) Progression-Free Survival (PRRT1) Progression 11 (100.0) Number of Therapies between PRRT1 and PRRT2 1 6 (54.5) 2 5 (45.5) Type (PRRT2) 177 Lu 11 (100.0) Number of Cycles (PRRT2) 1 3 (27.3) 2 2 (18.2) 3 3 (27.3) 4 3 (27.3) Restaging (PRRT2) Died 2 (18.2) PD 3 (27.3) PR 2 (18.2) SD 4 (36.4) Progression-Free Survival (PRRT2) Censored 1 (9.1) Progression 10 (90.9) Vital Status Alive 5 (45.5) Died 6 (54.5) Toxicity data Table 3 depicts a comparative analysis of toxicities after PRRT1 and PRRT2. We did not find a statistically significant difference between the occurrence of anemia, thrombocytopenia and renal toxicity after PRRT1 and PRRT2. While no patients developed grade 3 anemia after PRRT1 or PRRT2, 1 (10%) patient developed grade 3 thrombocytopenia after PRRT2. Median duration of follow up after PRRT2 was 11.3 months. No long-term hematological toxicities (acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)) were reported after PRRT1 or PRRT2. One patient each developed grade 3 renal toxicity after PRRT1 (9.1%) and PRRT2 (10%) and 1 patient developed grade 4 renal toxicity after PRRT1 ( 90 Y-DOTATOC). The patient most likely developed pre-renal acute kidney injury due to carcinoid crisis in the setting of underlying VIPoma and made full recovery eventually. The patient did not have any renal toxicity after repeat PRRT. No grade 4 renal toxicity events occurred after PRRT2. Response/efficacy At the first restaging scan after PRRT1 (3–6 months), 45.5%, 45.5% and 9.1% patients had partial response (PR), stable disease (SD) and progressive disease (PD) respectively. Median time duration between PRRT1 and PRRT2 was 36.1 months. All patients ultimately had progressive disease prior to PRRT2. At first restaging scan after PRRT2 (3–6 months), 18.2% (2/11), 36.4% (4/11) and 27.3% (3/11) patients had PR, SD and PD respectively; 2/11 patients (18.2%) died before first restaging scan. Median duration of follow up after PRRT2 was 11.3 months. PFS was not reached for one patient after PRRT2 and therefore was censored from the PFS analysis. Median PFS for PRRT1 (n = 11) was 25.4 months and median PFS (n = 10) for PRRT2 was 13.1 months. PFS for PRRT2 was significantly lower than PRRT1 (p = 0.001) [Figure 2 ]. As shown in Fig. 3 (A), the median PFS after PRRT2 for pancreatic NETs was not statistically different from PFS for small bowel NETs (13.1 months vs 11.3 months, p = 0.34). As shown in Fig. 3 (B), we also did not identify a statistically significant difference in median PFS after PRRT2 between functional and non-functional NETs (13.1 months vs 13.1 months, p = 0.43). Discussion To our knowledge, this is the first analysis describing the safety and effectiveness of repeat PRRT in a U.S. cohort of patients with NETs. We show that repeat PRRT may benefit select patients and has an acceptable safety profile. In our cohort, PFS was significantly lower after PRRT2 as compared to PRRT1. We did not find any differences in PFS after PRRT2 based on functionality or site of origin of NETs. Prior studies have reported mixed results with respect to objective response rates after PRRT2. In a retrospective analysis of 168 patients with bronchial or GEP NETs who underwent repeat PRRT, PR was recorded in 15.5% patients, while SD and PD were noted in 59.5% and 19.6% patients respectively [ 10 ]. In another retrospective analysis of 35 patients with advanced NETs, PR was observed in 3.1% patients; while 81.3% and 15.6% patients had SD and PD respectively [ 11 ]. The overall response rate with PRRT2 in our analysis was 18.2%, with 36.4% patients having SD after PRRT2. Overall, most patients appear to have SD or PR with PRRT2, however 27% have PD. Most prior studies appear to demonstrate a clinically meaningful PFS benefit with repeat PRRT. In a large random-effects meta-analysis of 13 clinical studies, the pooled PFS after repeat PRRT among patients who received 177 Lu-DOTATATE or 90 Y-DOTATOC for PRRT1 and 177 Lu-DOTATATE for PRRT2 was 12.5 months [ 12 ]. Similarly, the median PFS after PRRT2 in our analysis was 13.1 months. Similar to the results of the current analysis, prior studies also noted that the PFS after PRRT2 is significantly shorter than PFS after PRRT1 [ 13 ], [ 11 ]. We also captured data on acute (anemia and thrombocytopenia) and long-term (MDS/AML) hematological toxicities and renal toxicities after PRRT1 and PRRT2. In the NETTER-1 study investigating 177 Lu-DOTATATE PRRT in midgut NETs, no patients developed grade 3 or 4 anemia, while 2% patients developed grade 3 or 4 thrombocytopenia. Before the data cut off, only 1 patient developed MDS (0.9%) which was deemed to be related to the therapy. No new events of MDS/AML were reported in the updated analysis [ 2 ]. Prior retrospective studies have reported a 1–2% risk of long-term hematological toxicities in patients receiving PRRT [ 14 ], [ 15 ]. Retrospective studies evaluating the safety of repeat PRRT have indicated that the risk of acute hematological toxicities after repeat PRRT are comparable to first PRRT [ 10 ], [ 11 ]. In a pooled analysis of the studies reporting secondary malignancies with repeat PRRT, the incidence of MDS/AML was low; pooled incidence of 0% (95% CI 0–2) [ 12 ]. Similarly, in the current analysis, we did not detect a statistically significant difference in the incidence of acute hematological toxicities after PRRT1 and PRRT2. Additionally, none of the patients included in our analysis developed long term hematological toxicities after PRRT1 or PRRT2, although the follow up period after PRRT2 was rather limited. The introduction of 177 Lu-DOTATATE PRRT led to a significant reduction in the incidence of renal toxicity as compared to 90 Y-DOTATOC PRRT, the latter being associated with a high incidence (approximately 14%) of grade 3–4 renal toxicity [ 16 ]. Prior studies have reported no safety concerns with respect to renal toxicity, with low overall incidence of renal toxicity with repeat PRRT, particularly with 177 Lu-DOTATATE PRRT [ 10 ], [ 11 ]. In our study, we did not detect any statistically significant differences in incidence of renal toxicity after PRRT1 and PRRT2, despite more than half the patients in our cohort having received 90 Y-DOTATOC PRRT for PRRT1. Despite existing evidence regarding the safety and efficacy of repeat PRRT in the form of retrospective studies including ours, many questions regarding the application of these data to clinical practice remain unanswered. It is important to acknowledge that the safety and efficacy of repeat PRRT has not yet been formally investigated in a randomized controlled clinical trial. However, there are on-going trials such as NET RETREAT (NCT05773274) and ReLUTH (NCT04954820) evaluating the feasibility of salvage PRRT. Data from these clinical trials will not only help establish the clinical efficacy and safety of repeat PRRT but may also help identify patients who are more likely to benefit from repeat PRRT. There are also several advances in theranostics aiming to maximize the clinical benefit of PRRT. For example, PRRT utilizing alpha particle emitting nuclides (alpha PRRT) offers short radiation range and high linear energy transfer with greater DNA damage and reduced damage to surrounding normal tissue [ 17 ]. There are on-going alpha PRRT clinical trials, such as ACTION-1 (NCT05477576) evaluating the clinical efficacy and safety of 225 Ac-DOTATATE PRRT. Other clinical trials are ongoing to evaluate the clinical benefit of radiation sensitizing agents such as peposertib (NCT04750954) and triapine (NCT04234568), to maximize the clinical benefit of 177 Lu-DOTATATE PRRT. With the availability of these clinical trials, decision making regarding the sequencing of repeat 177 Lu-DOTATATE PRRT has become more challenging and requires careful multi-disciplinary discussion. Our study is limited by retrospective design and small sample size. The majority of the patients included had grade 1 well differentiated GEP NETs and therefore further studies with larger sample sizes and investigating repeat PRRT outcomes in a more diverse patient population are needed. In conclusion, our analysis offers retrospective experience demonstrating the clinical efficacy and safety of repeat PRRT in a U.S. cohort. While the results of ongoing clinical trials are awaited, repeat PRRT may be offered as a possible treatment option for patients with advanced and unresectable well differentiated NETs who have somatostatin receptor avid disease at progression and otherwise do not have any contraindications to PRRT. Declarations Conflicts of interest: None Funding: None Prior presentation: The current analysis was presented as an oral presentation at the North American Neuroendocrine Tumor Society (NANETS) annual symposium held in Montreal, Quebec, Canada in November, 2023. References Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol . 2018;31(12):1770-1786. Strosberg JR, Caplin ME, Kunz PL, et al. 177 Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial [published correction appears in Lancet Oncol. 2022 Feb;23(2):e59]. Lancet Oncol . 2021;22(12):1752-1763. Strosberg J, Wolin E, Chasen B, et al. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177 Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol . 2018;36(25):2578-2584. Brabander T, van der Zwan WA, Teunissen JJM, et al. Long-Term Efficacy, Survival, and Safety of [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clin Cancer Res . 2017;23(16):4617-4624. Shah MH, Goldner WS, Benson AB, et al. Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw . 2021;19(7):839-868. Hope TA, Bodei L, Chan JA, et al. NANETS/SNMMI Consensus Statement on Patient Selection and Appropriate Use of 177 Lu-DOTATATE Peptide Receptor Radionuclide Therapy. J Nucl Med . 2020;61(2):222-227. Del Rivero J, Perez K, Kennedy EB, et al. Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline. J Clin Oncol . 2023;41(32):5049-5067. Hicks RJ, Kwekkeboom DJ, Krenning E, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues. Neuroendocrinology . 2017;105(3):295-309. Prentice RL, Williams BJ, Peterson AV. On the regression analysis of multivariate failure time data. Biometrika 1981;68:373–79 van der Zwan WA, Brabander T, Kam BLR, et al. Salvage peptide receptor radionuclide therapy with [ 177 Lu-DOTA,Tyr 3 ]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging . 2019;46(3):704-717. Rudisile S, Gosewisch A, Wenter V, et al. Salvage PRRT with 177 Lu-DOTA-octreotate in extensively pretreated patients with metastatic neuroendocrine tumor (NET): dosimetry, toxicity, efficacy, and survival. BMC Cancer . 2019;19(1):788. Strosberg J, Leeuwenkamp O, Siddiqui MK. Peptide receptor radiotherapy re-treatment in patients with progressive neuroendocrine tumors: A systematic review and meta-analysis [published correction appears in Cancer Treat Rev. 2021 Jun;97:102203]. Cancer Treat Rev . 2021;93:102141. Zemczak A, Gut P, Pawlak D, et al. The Safety and Efficacy of the Repeated PRRT with [ 90 Y]Y/[ 177 Lu]Lu-DOTATATE in Patients with NET. Int J Endocrinol . 2021;2021:6615511. Bodei L, Kidd M, Paganelli G, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging . 2015;42(1):5-19. Sabet A, Ezziddin K, Pape UF, et al. Long-term hematotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med . 2013;54(11):1857-1861. Otte A, Herrmann R, Heppeler A, et al. Yttrium-90 DOTATOC: first clinical results. Eur J Nucl Med . 1999;26(11):1439-1447. Shi M, Jakobsson V, Greifenstein L, et al. Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists. Front Med (Lausanne) . 2022;9:1034315. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 04 Apr, 2024 Reviews received at journal 22 Mar, 2024 Reviewers agreed at journal 07 Mar, 2024 Reviewers invited by journal 06 Mar, 2024 Editor assigned by journal 06 Mar, 2024 Submission checks completed at journal 04 Mar, 2024 First submitted to journal 03 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4009283","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276144211,"identity":"8e6b1793-ecde-4f68-b78e-5472eeb322ca","order_by":0,"name":"Udhayvir S Grewal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIiWNgGAWjYFCCHBAhAeNZyDEwQ1iMDURqkTAmVgscSCTCVOLUYnA89+Bn3jaLfAb+tQ8f89RIpG84znxM4geDjeyGAzi0nHmXLM3bJmHZIPHc2JjnmETuhsNsaZI9DGnGOLXcyDGQ5jkjYWB/4xibdA4bSAuP2Q0ehsOJeLQY/wZpYZA4xv47559EugFQy80/DP/xaTGT5qkAauFvY2PObZNIAGm5zcNwAKcWyTNvzCzngLRIsDFL/+2TMJx5mC39t4xBsvFMHFr4jucY33hjUAe05RjjxxnfbOT5zh8+bPimwk62D4cWEGDiAZESCSgOxq0cBBh/gEh+PIaOglEwCkbByAYAgHVY3J5ZeC8AAAAASUVORK5CYII=","orcid":"","institution":"University of Iowa Hospitals and Clinics","correspondingAuthor":true,"prefix":"","firstName":"Udhayvir","middleName":"S","lastName":"Grewal","suffix":""},{"id":276144212,"identity":"cfa47424-61a0-4b0b-ad1d-a9deea123b16","order_by":1,"name":"Bradley T Loeffler","email":"","orcid":"","institution":"University of Iowa Holden Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Bradley","middleName":"T","lastName":"Loeffler","suffix":""},{"id":276144213,"identity":"88f31f8f-7119-48cc-9dc7-e807f30c8464","order_by":2,"name":"Alexander Paschke","email":"","orcid":"","institution":"University of Iowa Hospitals and Clinics","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Paschke","suffix":""},{"id":276144214,"identity":"8de6b23d-1bdf-458f-b568-c321cb10cb62","order_by":3,"name":"Joseph S. 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[PRRT: peptide receptor radionuclide therapy].\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4009283/v1/6f49b132b245de6cf7665316.png"},{"id":52107593,"identity":"4dc8cce9-936e-4e6f-83ac-fe99fa79ca10","added_by":"auto","created_at":"2024-03-06 19:55:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":67746,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan Meier curves for progression-free survival (PFS).\u003c/strong\u003e Median PFS after PRRT1 (n=11) was 25.4 months and median PFS (n=10) after PRRT2 was 13.1 months (p=0.001).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4009283/v1/b8c38bda486d187a911c0bd6.png"},{"id":52107592,"identity":"c7dea0a0-8736-4d87-9327-76648742f74b","added_by":"auto","created_at":"2024-03-06 19:55:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":172294,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan Meier curves for progression-free survival (PFS) after PRRT2\u003c/strong\u003e. (A) PFS for pancreatic NETs vs small bowel NETs (13.1 months vs 11.1 months, p=0.34). (B) PFS for functional vs non-functional NETs (13.1 months vs 13.1 months, p=0.43).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4009283/v1/8d1fdeb2bc05fa8f067deb19.png"},{"id":52107922,"identity":"280822ec-f890-4bef-adf4-4f1841b3ce6e","added_by":"auto","created_at":"2024-03-06 20:03:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":586285,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4009283/v1/28ed9ffb-1a60-42a1-b17e-5c64ef45a121.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Repeat Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors: A NET Center of Excellence Experience","fulltext":[{"header":"Background","content":"\u003cp\u003eNeuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies which are classified according to their site of origin and pathological characteristics such as grade and differentiation. Well-differentiated NENs are referred to as neuroendocrine tumors (NETs), which are further sub-classified based on their Ki-67 proliferation index into grade 1(Ki-67 1\u0026ndash;2%), grade 2 (Ki-67 3\u0026ndash;20%) and grade 3 (Ki-67\u0026thinsp;\u0026gt;\u0026thinsp;20%) NETs. Poorly differentiated NETs are referred to as neuroendocrine carcinomas (NECs) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePeptide receptor radionuclide therapy (PRRT) targets somatostatin receptor (SSTR) using somatostatin analogs (SSAs) that are labeled with radioactive isotopes. Yttrium-90 (\u003csup\u003e90\u003c/sup\u003eY) was previously used as a radiolabeling agent but was eventually replaced by Lutetium-177 (\u003csup\u003e177\u003c/sup\u003eLu) as the latter is associated with reduced renal toxicity. \u003csup\u003e177\u003c/sup\u003eLu-DOTATATE (Lutathera\u0026reg;) with octreotide long-acting release (LAR) 30 mg was shown to be associated with superior progression free survival (PFS) and quality of life in the phase III NETTER-1 study, compared to high dose octreotide LAR (60 mg once every 4 weeks) among patients with small bowel NETs; median PFS not reached in the PRRT arm compared to 8.4 months in the octreotide LAR alone arm (HR\u0026thinsp;=\u0026thinsp;0.21 95% CI 0.13 to 0.33, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A trend towards improved overall survival was also noted but this was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.30) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough the NETTER-1 study included only subjects with small bowel NETs, the US Food and Drug Administration (USFDA) approved the therapy for pancreatic NETs as well, based on prospective data from European centers [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. PRRT is endorsed as a potential therapeutic option for gastroenteropancreatic NETs, bronchial NETs and other rarer NETs such as paraganglioma or pheochromocytomas by the National Comprehensive Cancer Network (NCCN) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Various societies have recommendations in place regarding sequencing of PRRT with respect to other standard of care treatment options in patients with advanced NETs [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, due to a lack of robust prospective data regarding safety and feasibility, there is no direct guidance on the use of repeat (or salvage) PRRT in patients with NETs. The USFDA approval for \u003csup\u003e177\u003c/sup\u003eLu DOTATATE PRRT came through in 2018, however this treatment modality has been widely available in European nations since early 2000s. Therefore, the data for the safety and efficacy of repeat PRRT are almost exclusively from European centers. We present an updated experience with repeat PRRT in a cohort of US patients at our NET center of excellence.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe used our single-center longitudinal neuroendocrine tumor (NET) registry to identify patients who had been previously treated with at least one dose of PRRT (PRRT 1, either \u003csup\u003e177\u003c/sup\u003eLu DOTATATE or \u003csup\u003e90\u003c/sup\u003eY DOTATOC) and following radiographic disease progression (per RECIST 1.1 criteria) were re-treated with a second course of PRRT (PRRT 2). Study schema is highlighted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. We included patients with histological confirmation of grade 1 or grade 2 NET and metastatic disease, age\u0026thinsp;\u0026gt;\u0026thinsp;18 years, and performance status of ECOG 2 or better. Only patients with radiotracer avid disease on \u003csup\u003e68\u003c/sup\u003eGa- DOTATATE scan were included. Patients with poorly differentiated NEC or those who received alpha particle emitting PRRT were not included.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAll patients had evidence of acceptable hematological parameters and preserved liver and renal function prior to both PRRT1 and PRRT2. Per our institutional protocol, PRRT is offered only in patients with hemoglobin\u0026thinsp;\u0026gt;\u0026thinsp;8 gm/dL, platelet count\u0026thinsp;\u0026gt;\u0026thinsp;75,000 per cu. mm or estimated glomerular filtration rate\u0026thinsp;\u0026gt;\u0026thinsp;45 ml/min. All patients with functional syndromes continued SSAs between and after PRRT.\u003c/p\u003e \u003cp\u003eWe reviewed patient, tumor and treatment characteristics, objective response and toxicities after PRRT 1 and PRRT 2. The United States National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 was used for grading of toxicities.\u003c/p\u003e \u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki. All patients in the database provided informed consent in accordance with the protocol approved by the Institutional Review Board of the University of Iowa Holden Comprehensive Cancer Center (Iowa City).\u003c/p\u003e \u003cp\u003eFisher\u0026rsquo;s exact test was used to evaluate differences in the rate of toxicity between PRRT1 and PRRT2. Stratified Cox regression via the PWP Gap Time model for recurrent events proposed by Prentice, Williams, and Peterson was used to estimate the effect of disease characteristics on progression-free survival (PFS) after repeat PRRT [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. For assessing the progression free survival, time was computed from the start of PRRT to the date of progression or death due to any cause, or the date last known to be progression-free in the absence of progression. Survival probabilities were plotted along with 95% confidence intervals. Estimated effects were reported as hazard ratios (HR) along with 95% confidence intervals. All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom June 2018 to July 2023, a total of 153 patients received at least 1 dose of \u003csup\u003e177\u003c/sup\u003eLu DOTATATE PRRT at our institution post FDA approval, out of which, 13/153 (8.5%) patients received repeat PRRT. We excluded 2/13 patients due to lack of adequate follow up and included a total of 11 patients for the final analysis.\u003c/p\u003e\n\u003ch3\u003ePatient characteristics\u003c/h3\u003e\n\u003cp\u003eBaseline characteristics of the included patients are listed in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. All patients included were White (11/11, 100%). Mean age of the participants was 65.9 \u0026plusmn; 8.2 years and 54.5% (6/11) patients were males. Most patients had grade 2 (9/11, 81.8%) followed by grade 1 NET (2/11, 18.2%) and all except one patient included had gastroenteropancreatic origin NETs (10/11, 90.9%).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics of patients included in the final analysis [F: female, M: male, W: white, NF: non-functional].\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLevel\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRace\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003ePrimary Site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePancreas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmall Bowel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnclear Origin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eFunctional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFunctional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eGrade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9 (81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"6\"\u003e\n \u003cp\u003eNumber of Prior Therapies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eTreatment characteristics\u003c/h3\u003e\n\u003cp\u003e45.5% (5/11) patients received \u003csup\u003e177\u003c/sup\u003e Lu DOTATATE PRRT only, both for PRRT1 and PRRT 2, while 54.5% (6/11) patients received \u003csup\u003e90\u003c/sup\u003eY DOTATOC PRRT for PRRT1. Median number of lines therapies before PRRT1 and between PRRT1 and PRRT2 were 2 (IQR 2,5) and 1 (IQR 1,2) respectively. Median time duration between PRRT1 and PRRT2 was 36.1 months. Patients received a median of 3 (IQR 2, 4) and 3 (IQR 1,4) cycles for PRRT1 and PRRT2 respectively. Median radioactive dose with PRRT1 and PRRT2 was 176 mCi and 196 mCi respectively. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e highlights treatment characteristics for the patients included in the analysis.\u003c/p\u003e\n\u003cdiv\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Treatment characteristics and outcomes for patients included in the analysis. [PRRT: peptide receptor radionuclide therapy, PD: progressive disease, PR: partial response, SD: stable disease].\u0026nbsp;\u003c/div\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Level\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eN = 11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eType (PRRT1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003csup\u003e177\u003c/sup\u003eLu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003csup\u003e90\u003c/sup\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eNumber of Cycles (PRRT1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eRestaging (PRRT1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eProgression-Free Survival (PRRT1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNumber of Therapies between PRRT1 and PRRT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eType (PRRT2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003csup\u003e177\u003c/sup\u003eLu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eNumber of Cycles (PRRT2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eRestaging (PRRT2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eProgression-Free Survival (PRRT2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCensored\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (90.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eVital Status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDied\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/122228_c8a1650c59388082/122228_custom_files/img1709707792.png\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv\u003eToxicity data\u003c/div\u003e\n\u003cp\u003eTable\u0026nbsp;3 depicts a comparative analysis of toxicities after PRRT1 and PRRT2. We did not find a statistically significant difference between the occurrence of anemia, thrombocytopenia and renal toxicity after PRRT1 and PRRT2. While no patients developed grade 3 anemia after PRRT1 or PRRT2, 1 (10%) patient developed grade 3 thrombocytopenia after PRRT2. Median duration of follow up after PRRT2 was 11.3 months. No long-term hematological toxicities (acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)) were reported after PRRT1 or PRRT2. One patient each developed grade 3 renal toxicity after PRRT1 (9.1%) and PRRT2 (10%) and 1 patient developed grade 4 renal toxicity after PRRT1 (\u003csup\u003e90\u003c/sup\u003eY-DOTATOC). The patient most likely developed pre-renal acute kidney injury due to carcinoid crisis in the setting of underlying VIPoma and made full recovery eventually. The patient did not have any renal toxicity after repeat PRRT. No grade 4 renal toxicity events occurred after PRRT2.\u003c/p\u003e\n\u003ch3\u003eResponse/efficacy\u003c/h3\u003e\n\u003cp\u003eAt the first restaging scan after PRRT1 (3\u0026ndash;6 months), 45.5%, 45.5% and 9.1% patients had partial response (PR), stable disease (SD) and progressive disease (PD) respectively. Median time duration between PRRT1 and PRRT2 was 36.1 months. All patients ultimately had progressive disease prior to PRRT2. At first restaging scan after PRRT2 (3\u0026ndash;6 months), 18.2% (2/11), 36.4% (4/11) and 27.3% (3/11) patients had PR, SD and PD respectively; 2/11 patients (18.2%) died before first restaging scan. Median duration of follow up after PRRT2 was 11.3 months. PFS was not reached for one patient after PRRT2 and therefore was censored from the PFS analysis. Median PFS for PRRT1 (n\u0026thinsp;=\u0026thinsp;11) was 25.4 months and median PFS (n\u0026thinsp;=\u0026thinsp;10) for PRRT2 was 13.1 months. PFS for PRRT2 was significantly lower than PRRT1 (p\u0026thinsp;=\u0026thinsp;0.001) [Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e]. As shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e (A), the median PFS after PRRT2 for pancreatic NETs was not statistically different from PFS for small bowel NETs (13.1 months vs 11.3 months, p\u0026thinsp;=\u0026thinsp;0.34). As shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e (B), we also did not identify a statistically significant difference in median PFS after PRRT2 between functional and non-functional NETs (13.1 months vs 13.1 months, p\u0026thinsp;=\u0026thinsp;0.43).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first analysis describing the safety and effectiveness of repeat PRRT in a U.S. cohort of patients with NETs. We show that repeat PRRT may benefit select patients and has an acceptable safety profile. In our cohort, PFS was significantly lower after PRRT2 as compared to PRRT1. We did not find any differences in PFS after PRRT2 based on functionality or site of origin of NETs.\u003c/p\u003e \u003cp\u003ePrior studies have reported mixed results with respect to objective response rates after PRRT2. In a retrospective analysis of 168 patients with bronchial or GEP NETs who underwent repeat PRRT, PR was recorded in 15.5% patients, while SD and PD were noted in 59.5% and 19.6% patients respectively [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In another retrospective analysis of 35 patients with advanced NETs, PR was observed in 3.1% patients; while 81.3% and 15.6% patients had SD and PD respectively [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The overall response rate with PRRT2 in our analysis was 18.2%, with 36.4% patients having SD after PRRT2. Overall, most patients appear to have SD or PR with PRRT2, however 27% have PD.\u003c/p\u003e \u003cp\u003eMost prior studies appear to demonstrate a clinically meaningful PFS benefit with repeat PRRT. In a large random-effects meta-analysis of 13 clinical studies, the pooled PFS after repeat PRRT among patients who received \u003csup\u003e177\u003c/sup\u003eLu-DOTATATE or \u003csup\u003e90\u003c/sup\u003eY-DOTATOC for PRRT1 and \u003csup\u003e177\u003c/sup\u003eLu-DOTATATE for PRRT2 was 12.5 months [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Similarly, the median PFS after PRRT2 in our analysis was 13.1 months. Similar to the results of the current analysis, prior studies also noted that the PFS after PRRT2 is significantly shorter than PFS after PRRT1 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe also captured data on acute (anemia and thrombocytopenia) and long-term (MDS/AML) hematological toxicities and renal toxicities after PRRT1 and PRRT2. In the NETTER-1 study investigating \u003csup\u003e177\u003c/sup\u003eLu-DOTATATE PRRT in midgut NETs, no patients developed grade 3 or 4 anemia, while 2% patients developed grade 3 or 4 thrombocytopenia. Before the data cut off, only 1 patient developed MDS (0.9%) which was deemed to be related to the therapy. No new events of MDS/AML were reported in the updated analysis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Prior retrospective studies have reported a 1\u0026ndash;2% risk of long-term hematological toxicities in patients receiving PRRT [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Retrospective studies evaluating the safety of repeat PRRT have indicated that the risk of acute hematological toxicities after repeat PRRT are comparable to first PRRT [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In a pooled analysis of the studies reporting secondary malignancies with repeat PRRT, the incidence of MDS/AML was low; pooled incidence of 0% (95% CI 0\u0026ndash;2) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Similarly, in the current analysis, we did not detect a statistically significant difference in the incidence of acute hematological toxicities after PRRT1 and PRRT2. Additionally, none of the patients included in our analysis developed long term hematological toxicities after PRRT1 or PRRT2, although the follow up period after PRRT2 was rather limited.\u003c/p\u003e \u003cp\u003eThe introduction of \u003csup\u003e177\u003c/sup\u003eLu-DOTATATE PRRT led to a significant reduction in the incidence of renal toxicity as compared to \u003csup\u003e90\u003c/sup\u003eY-DOTATOC PRRT, the latter being associated with a high incidence (approximately 14%) of grade 3\u0026ndash;4 renal toxicity [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Prior studies have reported no safety concerns with respect to renal toxicity, with low overall incidence of renal toxicity with repeat PRRT, particularly with \u003csup\u003e177\u003c/sup\u003eLu-DOTATATE PRRT [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In our study, we did not detect any statistically significant differences in incidence of renal toxicity after PRRT1 and PRRT2, despite more than half the patients in our cohort having received \u003csup\u003e90\u003c/sup\u003eY-DOTATOC PRRT for PRRT1.\u003c/p\u003e \u003cp\u003eDespite existing evidence regarding the safety and efficacy of repeat PRRT in the form of retrospective studies including ours, many questions regarding the application of these data to clinical practice remain unanswered. It is important to acknowledge that the safety and efficacy of repeat PRRT has not yet been formally investigated in a randomized controlled clinical trial. However, there are on-going trials such as NET RETREAT (NCT05773274) and ReLUTH (NCT04954820) evaluating the feasibility of salvage PRRT. Data from these clinical trials will not only help establish the clinical efficacy and safety of repeat PRRT but may also help identify patients who are more likely to benefit from repeat PRRT. There are also several advances in theranostics aiming to maximize the clinical benefit of PRRT. For example, PRRT utilizing alpha particle emitting nuclides (alpha PRRT) offers short radiation range and high linear energy transfer with greater DNA damage and reduced damage to surrounding normal tissue [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. There are on-going alpha PRRT clinical trials, such as ACTION-1 (NCT05477576) evaluating the clinical efficacy and safety of \u003csup\u003e225\u003c/sup\u003eAc-DOTATATE PRRT. Other clinical trials are ongoing to evaluate the clinical benefit of radiation sensitizing agents such as peposertib (NCT04750954) and triapine (NCT04234568), to maximize the clinical benefit of \u003csup\u003e177\u003c/sup\u003eLu-DOTATATE PRRT. With the availability of these clinical trials, decision making regarding the sequencing of repeat \u003csup\u003e177\u003c/sup\u003eLu-DOTATATE PRRT has become more challenging and requires careful multi-disciplinary discussion.\u003c/p\u003e \u003cp\u003eOur study is limited by retrospective design and small sample size. The majority of the patients included had grade 1 well differentiated GEP NETs and therefore further studies with larger sample sizes and investigating repeat PRRT outcomes in a more diverse patient population are needed.\u003c/p\u003e \u003cp\u003eIn conclusion, our analysis offers retrospective experience demonstrating the clinical efficacy and safety of repeat PRRT in a U.S. cohort. While the results of ongoing clinical trials are awaited, repeat PRRT may be offered as a possible treatment option for patients with advanced and unresectable well differentiated NETs who have somatostatin receptor avid disease at progression and otherwise do not have any contraindications to PRRT.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eConflicts of interest: None\u003c/p\u003e\n\u003cp\u003eFunding: None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrior presentation:\u003c/strong\u003e The current analysis was presented as an oral presentation at the North American Neuroendocrine Tumor Society (NANETS) annual symposium held in Montreal, Quebec, Canada in November, 2023.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. \u003cem\u003eMod Pathol\u003c/em\u003e. 2018;31(12):1770-1786.\u003c/li\u003e\n\u003cli\u003eStrosberg JR, Caplin ME, Kunz PL, et al. \u003csup\u003e177\u003c/sup\u003eLu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial [published correction appears in Lancet Oncol. 2022 Feb;23(2):e59]. \u003cem\u003eLancet Oncol\u003c/em\u003e. 2021;22(12):1752-1763.\u003c/li\u003e\n\u003cli\u003eStrosberg J, Wolin E, Chasen B, et al. 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NANETS/SNMMI Consensus Statement on Patient Selection and Appropriate Use of \u003csup\u003e177\u003c/sup\u003eLu-DOTATATE Peptide Receptor Radionuclide Therapy. \u003cem\u003eJ Nucl Med\u003c/em\u003e. 2020;61(2):222-227. \u003c/li\u003e\n\u003cli\u003eDel Rivero J, Perez K, Kennedy EB, et al. Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2023;41(32):5049-5067. \u003c/li\u003e\n\u003cli\u003eHicks RJ, Kwekkeboom DJ, Krenning E, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues. \u003cem\u003eNeuroendocrinology\u003c/em\u003e. 2017;105(3):295-309. \u003c/li\u003e\n\u003cli\u003ePrentice RL, Williams BJ, Peterson AV. On the regression analysis of multivariate failure time data. \u003cem\u003eBiometrika\u003c/em\u003e1981;68:373\u0026ndash;79\u003c/li\u003e\n\u003cli\u003evan der Zwan WA, Brabander T, Kam BLR, et al. Salvage peptide receptor radionuclide therapy with [\u003csup\u003e177\u003c/sup\u003eLu-DOTA,Tyr\u003csup\u003e3\u003c/sup\u003e]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours. \u003cem\u003eEur J Nucl Med Mol Imaging\u003c/em\u003e. 2019;46(3):704-717.\u003c/li\u003e\n\u003cli\u003eRudisile S, Gosewisch A, Wenter V, et al. Salvage PRRT with \u003csup\u003e177\u003c/sup\u003eLu-DOTA-octreotate in extensively pretreated patients with metastatic neuroendocrine tumor (NET): dosimetry, toxicity, efficacy, and survival. \u003cem\u003eBMC Cancer\u003c/em\u003e. 2019;19(1):788. \u003c/li\u003e\n\u003cli\u003eStrosberg J, Leeuwenkamp O, Siddiqui MK. 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Long-term hematotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate. \u003cem\u003eJ Nucl Med\u003c/em\u003e. 2013;54(11):1857-1861. \u003c/li\u003e\n\u003cli\u003eOtte A, Herrmann R, Heppeler A, et al. Yttrium-90 DOTATOC: first clinical results. \u003cem\u003eEur J Nucl Med\u003c/em\u003e. 1999;26(11):1439-1447.\u003c/li\u003e\n\u003cli\u003eShi M, Jakobsson V, Greifenstein L, et al. Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists. \u003cem\u003eFront Med (Lausanne)\u003c/em\u003e. 2022;9:1034315. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4009283/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4009283/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eThe available data for the safety and efficacy of repeat Peptide Receptor Radionuclide Therapy (PRRT) are almost exclusively from European centers. We present an updated experience with repeat PRRT in a cohort of US patients with neuroendocrine tumors (NETs) at our NET center of excellence.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe used our single-center longitudinal NET registry to identify patients who had been previously treated with at least one dose of PRRT (PRRT 1, either \u003csup\u003e177\u003c/sup\u003eLu DOTATATE or \u003csup\u003e90\u003c/sup\u003eY DOTATOC) and following radiographic disease progression (per RECIST 1.1 criteria) were re-treated with a second course of PRRT (PRRT 2). We reviewed patient, tumor and treatment characteristics, objective response rates and toxicities after PRRT 1 and PRRT 2.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 11 patients were included in the analysis. 45.5% (5/11) patients received \u003csup\u003e177\u003c/sup\u003e Lu DOTATATE PRRT only, both for PRRT1 and PRRT 2, while 54.5% (6/11) patients received \u003csup\u003e90\u003c/sup\u003eY DOTATOC PRRT for PRRT1. At first restaging scan after PRRT2 (3\u0026ndash;6 months), 18.2% (2/11), 36.4% (4/11) and 27.3% (3/11) patients had PR, SD and PD respectively; 2/11 patients (18.2%) died before first restaging scan. Median PFS for PRRT1 (n\u0026thinsp;=\u0026thinsp;11) was 25.4 months and median PFS (n\u0026thinsp;=\u0026thinsp;10) for PRRT2 was 13.1 months (p\u0026thinsp;=\u0026thinsp;0.0001). We did not find a statistically significant difference between the occurrence of short and long-term hematological toxicities as well as renal toxicity after PRRT1 and PRRT2.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eWe show that repeat PRRT may benefit select patients and has an acceptable safety profile. In our cohort, PFS was significantly lower after PRRT2 as compared to PRRT1.\u003c/p\u003e","manuscriptTitle":"Repeat Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors: A NET Center of Excellence Experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-06 19:55:52","doi":"10.21203/rs.3.rs-4009283/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-04T17:29:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-22T08:40:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"f793de03-1ca1-4698-b967-2bbd4dee6aa3","date":"2024-03-07T23:51:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-07T02:06:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-07T02:02:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-04T05:51:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Gastrointestinal Cancer","date":"2024-03-03T16:52:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5a15f697-be45-4a5a-8d7f-4669f174475b","owner":[],"postedDate":"March 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-05-05T00:54:31+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-06 19:55:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4009283","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4009283","identity":"rs-4009283","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}