Comparison of the Hematotoxicity of PRRT with Lutathera® and Locally Manufactured 177Lu-HA-DOTATATE in Patients with Neuroendocrine Tumors and the Impact of Different Application Intervals
Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patient Enrollment
2.2. Radiopeptides
2.3. 177Lu-HA-DOTATATE Treatment
2.4. Evaluation of Toxicity
2.5. Statistical Analysis
3. Results
3.1. Radiolabelling
3.2. Patients
3.3. Therapy Associated Toxicity During PRRT
3.3.1. CTCAE Assessment
3.3.2. Comparison of Absolute Blood Counts Before and After PRRT Within Each Subgroup
3.3.3. Comparison of Percentage Changes in Hematological and Renal Parameters Between the Subgroups
Hemoglobin, Creatinine and TER
WBC Counts
PLT Counts
- HA8weeks: HA8weeks patients presented a significantly higher reduction (%) of PLT counts at follow-up 1 in contrast to values prior to PRRT when compared to the Lutathera8weeks group (HA8weeks = −34.7 ± 16.9 vs. Lutathera8weeks = −15.1 ± 14.5 [%]; p = 0.023). Moreover, patients of the HA8weeks group also showed a significantly higher decline (%) of PLT counts at follow-up 2 in comparison to values prior to PRRT when compared to Lutathera8weeks patients (HA8weeks = −48.3 ± 16.9 vs. Lutathera8weeks = −24.1 ± 15.1 [%]; p = 0.003) as well as when compared to patients of Lutatheraadapted (HA8weeks = −48.3 ± 16.9 vs. Lutatheraadapted = −28.3 ± 17.2 [%]; p = 0.042) (Figure 1).
- HAadapted: A significantly higher decline (%) of PLT counts in between follow-up 1 and follow-up 2 was measured in HAadapted patients in comparison to Lutatheraadapted patients (HAadapted = −32.1 ± 30.2 vs. Lutatheraadapted = −6.8 ± 17.1 [%], p = 0.005) as well as in comparison to Lutathera8weeks patients (HAadapted = −32.1 ± 30.2 vs. Lutathera8weeks = −15.1 ± 14.5 [%], p = 0.01). HAadapted patients also demonstrated a significantly higher decline (%) of PLT counts at follow-up 2 (HAadapted = −46.1 ± 22.9 vs. Lutathera8weeks = −24.1 ± 15.1 [%], p = 0.008) when compared to baseline values of Lutathera8weeks patients (Figure 1).
3.3.4. Recovery Trends of Hematological and Renal Parameters of All Therapy Subgroups
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Riihimäki, M.; Hemminki, A.; Sundquist, K.; Sundquist, J.; Hemminki, K. The epidemiology of metastases in neuroendocrine tumors. Int. J. Cancer. 2016, 139, 2679–2686. [Google Scholar] [CrossRef]
- Oronsky, B.; Ma, P.C.; Morgensztern, D.; Carter, C.A. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia 2017, 19, 991–1002. [Google Scholar] [CrossRef] [PubMed]
- Federführende Fachgesellschaft: Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS); Beteiligte Fachgesellschaften: Netzwerk Neuroendokrine Tumoren (NeT) e.V. (Patientenvertretung); Bundesorganisation Selbsthilfe NeuroEndokrine Tumoren e.V. (NET-sgh) (Patientenvertretung); Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e.V. (DGHO); Arbeitsgemeinschaft Internistische Onkologie (AIO) der Deutschen Krebsgesellschaft e.V; Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie e.V. (DGAV); Deutsche Gesellschaft für Chirurgie (DGCH); Deutsche Gesellschaft für Endoskopie und Bildgebende Verfahren (DGEBV); Deutsche Gesellschaft für Nuklearmedizin e.V. (DGNM); Deutsche Gesellschaft für Innere Medizin (DGIM); et al. S2k-Leitlinie Neuroendokrine Tumore. Z. Gastroenterol. 2018, 56, 583–681. [Google Scholar] [CrossRef] [PubMed]
- Falconi, M.; Eriksson, B.; Kaltsas, G.; Bartsch, D.K.; Capdevila, J.; Caplin, M.; Kos-Kudla, B.; Kwekkeboom, D.; Rindi, G.; Klöppel, G.; et al. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology 2016, 103, 153–171. [Google Scholar] [CrossRef]
- Garcia-Carbonero, R.; Sorbye, H.; Baudin, E.; Raymond, E.; Wiedenmann, B.; Niederle, B.; Sedlackova, E.; Toumpanakis, C.; Anlauf, M.; Cwikla, J.M.; et al. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. Neuroendocrinology 2016, 103, 186–194. [Google Scholar] [CrossRef] [PubMed]
- Strosberg, J.R.; Caplin, M.E.; Kunz, P.L.; Ruszniewski, P.B.; Bodei, L.; Hendifar, A.; Mittra, E.; Wolin, E.M.; Yao, J.C.; Pavel, M.E.; et al. 177Lu-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. Lancet Oncol. 2021, 22, 1752–1763. [Google Scholar] [CrossRef]
- Hennrich, U.; Kopka, K. Lutathera®: The First FDA- and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy. Pharmaceuticals 2019, 12, 114. [Google Scholar] [CrossRef]
- Advanced Accelerator Applications. Lutathera® Summary of Product Characteristics. Available online: https://www.ema.europa.eu/en/documents/product-information/lutathera-epar-product-information_en.pdf (accessed on 7 February 2023).
- Das, S.; Al-Toubah, T.; El-Haddad, G.; Strosberg, J. 177Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors. Expert. Rev. Gastroenterol. Hepatol. 2019, 13, 1023–1031. [Google Scholar] [CrossRef]
- Advanced Accelerator Applications. Product Monograph LUTATHERA®. Available online: https://www.samnordic.se/wp-content/uploads/2018/05/LUTATHERA-MONOGRAPH-120218.pdf (accessed on 7 February 2023).
- Brogsitter, C.; Schottelius, M.; Zöphel, K.; Kotzerke, J.; Wester, H.J. Twins in spirit: DOTATATE and high-affinity DOTATATE. Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 1789. [Google Scholar] [CrossRef]
- Shaheen, S.; Moradi, F.; Gamino, G.; Kunz, P.L. Patient Selection and Toxicities of PRRT for Metastatic Neuroendocrine Tumors and Research Opportunities. Curr. Treat. Options Oncol. 2020, 21, 25. [Google Scholar] [CrossRef]
- Becx, M.N.; Minczeles, N.S.; Brabander, T.; Herder WW de Nonnekens, J.; Hofland, J. A Clinical Guide to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in Neuroendocrine Tumor Patients. Cancers 2022, 14, 5792. [Google Scholar] [CrossRef] [PubMed]
- Bergsma, H.; Konijnenberg, M.W.; Kam, B.L.R.; Teunissen, J.J.M.; Kooij, P.P.; de Herder, W.W.; Franssen, G.J.H.; van Eijck, C.H.J.; Krenning, E.P.; Kwekkeboom, D.J. Subacute haematotoxicity after PRRT with 177Lu-DOTA-octreotate: Prognostic factors, incidence and course. Eur. J. Nucl. Med. Mol. Imaging 2016, 43, 453–463. [Google Scholar] [CrossRef] [PubMed]
- Geenen, L.; Nonnekens, J.; Konijnenberg, M.; Baatout, S.; De Jong, M.; Aerts, A. Overcoming nephrotoxicity in peptide receptor radionuclide therapy using 177LuLu-DOTA-TATE for the treatment of neuroendocrine tumours. Nucl. Med. Biol. 2021, 102–103, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Bodei, L.; Schöder, H.; Baum, R.P.; Herrmann, K.; Strosberg, J.; Caplin, M.; Öberg, K.; Modlin, I.M. Molecular profiling of neuroendocrine tumours to predict response and toxicity to peptide receptor radionuclide therapy. Lancet Oncol. 2020, 21, e431–e443. [Google Scholar] [CrossRef]
- Bodei, L.; Cremonesi, M.; Ferrari, M.; Pacifici, M.; Grana, C.M.; Bartolomei, M.; Baio, S.M.; Sansovini, M.; Paganelli, G. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: The role of associated risk factors. Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 1847–1856. [Google Scholar] [CrossRef]
- Hope, T.A.; Bodei, L.; Chan, J.A.; El-Haddad, G.; Fidelman, N.; Kunz, P.L.; Mailman, J.; Menda, Y.; Metz, D.C.; Mittra, E.S.; et al. NANETS/SNMMI Consensus Statement on Patient Selection and Appropriate Use of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy. J. Nucl. Med. 2020, 61, 222–227. [Google Scholar] [CrossRef]
- Ilhan, H.; Wang, H.; Gildehaus, F.J.; Wängler, C.; Herrler, T.; Todica, A.; Schlichtiger, J.; Cumming, P.; Bartenstein, P.; Hacker, M.; et al. Nephroprotective effects of enalapril after 177Lu-DOTATATE therapy using serial renal scintigraphies in a murine model of radiation-induced nephropathy. EJNMMI Res. 2016, 6, 64. [Google Scholar] [CrossRef]
- de Vries–Huizing, D.M.V.; Versleijen, M.W.J.; Sinaasappel, M.; Walraven, I.; Geluk–Jonker, M.M.; Tesselaar, M.E.T.; Hendrikx, J.J.M.A.; Veen, B.J.d.W.d.; Stokkel, M.P.M. Haematotoxicity during peptide receptor radionuclide therapy: Baseline parameters differences and effect on patient’s therapy course. PLoS ONE 2021, 16, e0260073. [Google Scholar] [CrossRef]
- Garske-Román, U.; Sandström, M.; Fröss Baron, K.; Lundin, L.; Hellman, P.; Welin, S.; Johansson, S.; Khan, T.; Lundqvist, H.; Eriksson, B.; et al. Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): Feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity. Eur. J. Nucl. Med. Mol. Imaging 2018, 45, 970–988. [Google Scholar] [CrossRef]
- Svensson, J.; Berg, G.; Wängberg, B.; Larsson, M.; Forssell-Aronsson, E.; Bernhardt, P. Renal function affects absorbed dose to the kidneys and haematological toxicity during 177Lu-DOTATATE treatment. Eur. J. Nucl. Med. Mol. Imaging 2015, 42, 947–955. [Google Scholar] [CrossRef]
- Fröss-Baron, K.; Garske-Roman, U.; Welin, S.; Granberg, D.; Eriksson, B.; Khan, T.; Sandström, M.; Sundin, A. 177Lu-DOTATATE Therapy of Advanced Pancreatic Neuroendocrine Tumors Heavily Pretreated with Chemotherapy: Analysis of Outcome, Safety, and Their Determinants. Neuroendocrinology 2021, 111, 330–343. [Google Scholar] [CrossRef] [PubMed]
- Chantadisai, M.; Kulkarni, H.R.; Baum, R.P. Therapy-related myeloid neoplasm after peptide receptor radionuclide therapy (PRRT) in 1631 patients from our 20 years of experiences: Prognostic parameters and overall survival. Eur. J. Nucl. Med. Mol. Imaging 2021, 48, 1390–1398. [Google Scholar] [CrossRef] [PubMed]
- Sonbol, M.B.; Halfdanarson, T.R.; Hilal, T. Assessment of Therapy-Related Myeloid Neoplasms in Patients With Neuroendocrine Tumors After Peptide Receptor Radionuclide Therapy: A Systematic Review. JAMA Oncol. 2020, 6, 1086–1092. [Google Scholar] [CrossRef] [PubMed]
- Goncalves, I.; Burbury, K.; Michael, M.; Iravani, A.; Kumar, A.S.R.; Akhurst, T.; Tiong, I.S.; Blombery, P.; Hofman, M.S.; Westerman, D.; et al. Characteristics and outcomes of therapy-related myeloid neoplasms after peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) for metastatic neuroendocrine neoplasia: A single-institution series. Eur. J. Nucl. Med. Mol. Imaging 2019, 46, 1902–1910. [Google Scholar] [CrossRef]
- Travaglini, S.; Marinoni, M.; Visconte, V.; Guarnera, L. Therapy-Related Myeloid Neoplasm: Biology and Mechanistic Aspects of Malignant Progression. Biomedicines 2024, 12, 1054. [Google Scholar] [CrossRef]
Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
---|---|---|---|---|
PLT count decreased | <LLN to 75.000/µL | 50.000–75.000/µL | 25.000–50.000/µL | <25.000/µL |
Anemia | <LLN to 10 g/dL | 8.0–10.0 g/dL | <8.0 g/dL | life-threatening consequences |
Neutrophil count decreased | <LLN to 1.500/µL | 1.000–1.500/µL | 500–1.000/µL | <500/µL |
Lymphocyte count decreased | <LLN to 800/µL | 500–800/µL | 200–500/µL | <200/µL |
(Mean ± SD) | All | Lutathera8weeks | Lutatheraadapted | HA8weeks | HAadapted | p-Value |
---|---|---|---|---|---|---|
n | 46 | 16 | 10 | 10 | 10 | |
Sex | ♂ 22 ♀ 24 | ♂ 10 ♀ 6 | ♂ 3 ♀ 7 | ♂ 5 ♀ 5 | ♂ 4 ♀ 6 | 0.426 |
Age [y] | 66.5 ± 0.7 | 67.5 ± 12 | 65.9 ± 11 | 66.1 ± 13 | 66.6 ± 11 | 0.985 |
Time since initial diagnosis [m] | 47.6 ± 16 | 64.1 ± 66 | 57.5 ± 42 | 40.5 ± 48 | 28.3 ± 34 | 0.337 |
Ki-67 [%] | 7.3 ± 1.6 | 7 ± 6 | 5.7 ± 3 | 9.6 ± 5 | 7 ± 6 | 0.431 |
Grading | G1 n = 11, G2 n = 35 | G1 n = 4, G2 n = 12 | G1 n = 3, G2 n = 7 | G1 n = 2, G2 n = 8 | G1 n = 2, G2 n = 8 | 0.944 |
Anemia | Thrombocytopenia | Neutropenia | Lymphocytopenia | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTCAE grade | 1 | 2 | 3 | 1 | 2 | 3 | 1 | 2 | 3 | 1 | 2 | 3 | 4 |
Prior to PRRT | |||||||||||||
Lutathera8weeks | - | - | - | - | - | - | - | - | - | 4 | - | - | - |
Lutatheraadapted | 1 | - | - | - | - | - | 1 | - | - | 3 | 1 | - | - |
HA8weeks | 1 | - | - | - | - | - | - | - | - | 2 | - | - | - |
HAadapted | - | - | - | - | - | - | - | - | - | 1 | 1 | - | - |
After 4 cycles of PRRT | |||||||||||||
Lutathera8weeks | 8 | - | - | 4 | - | - | 1 | - | - | 1 | 1 | 7 | - |
Lutatheraadapted | 4 | 2 | - | 3 | - | - | 1 | 1 | - | - | 3 | 3 | 1 |
HA8weeks | 2 | 1 | - | 7 | - | - | - | 1 | - | 2 | 6 | 2 | - |
HAadapted | 3 | 1 | - | 4 | 1 | 1 | 1 | 1 | - | 2 | - | 8 | - |
Lutathera8weeks Prior to PRRT vs. Lutathera8weeks After PRRT | Lutatheraadapted Prior to PRRT vs. Lutatheraadapted After PRRT | HA8weeks Prior to PRRT vs. HA8weeks After PRRT | HAadapted Prior to PRRT vs. HAadapted After PRRT | |
---|---|---|---|---|
Hemoglobin [mg/dL] | 13.73 vs. 12.36, p = 0.011 | 12.75 vs. 11.27, p = 0.062 | 13.8 vs. 11.25, p = 0.02 | 13.66 vs. 11.82, p = 0.041 |
PLT counts [G/L] | 273.3 vs. 202.8, p = 0.024 | 256.8 vs. 181, p = 0.017 | 281.3 vs. 143.5, p ≤ 0.0001 | 271.3 vs. 139.6, p = 0.001 |
WBC counts [G/L] | 7.0 vs. 4.79, p = 0.002 | 6.63 vs. 4.32, p = 0.021 | 6.78 vs. 4.25, p = 0.001 | 6.93 vs. 3.43, p ≤ 0.0001 |
Neutrophile granulocytes [G/L] | 4.61 vs. 3.45, p = 0.01 | 4.48 vs. 3.0, p = 0.027 | 4.45 vs. 2.89, p = 0.009 | 4.4 vs. 2.44, p = 0.001 |
Lymphocytes [G/L] | 1.38 vs. 0.54, p = 0.02 | 1.21 vs. 0.57, p = 0.01 | 1.54 vs. 0.68, p ≤ 0.0001 | 1.81 vs. 0.43, p ≤ 0.0001 |
Creatinine [mg/dL] | 0.9 vs. 0.87, p = 0.36 | 0.77 vs. 0.82, p = 0.566 | 0.85 vs. 0.85, p = 0.989 | 0.79 vs. 0.8, p = 0.881 |
Total-TER [mL/min] | 201.9 vs. 191.3, p = 0.627 | 217.5 vs. 210.5, p = 0.288 | 211.4 vs. 189, p = 0.357 | 228.4 vs. 210.7, p = 0.365 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Hofmann, M.; Kunte, S.C.; Unterrainer, M.; Delker, A.; Holzgreve, A.; Toms, J.; Gildehaus, F.J.; Auernhammer, C.J.; Spitzweg, C.; Zacherl, M.J.; et al. Comparison of the Hematotoxicity of PRRT with Lutathera® and Locally Manufactured 177Lu-HA-DOTATATE in Patients with Neuroendocrine Tumors and the Impact of Different Application Intervals. Cancers 2025, 17, 1423. https://doi.org/10.3390/cancers17091423
Hofmann M, Kunte SC, Unterrainer M, Delker A, Holzgreve A, Toms J, Gildehaus FJ, Auernhammer CJ, Spitzweg C, Zacherl MJ, et al. Comparison of the Hematotoxicity of PRRT with Lutathera® and Locally Manufactured 177Lu-HA-DOTATATE in Patients with Neuroendocrine Tumors and the Impact of Different Application Intervals. Cancers. 2025; 17(9):1423. https://doi.org/10.3390/cancers17091423
Chicago/Turabian StyleHofmann, Markus, Sophie C. Kunte, Marcus Unterrainer, Astrid Delker, Adrien Holzgreve, Johannes Toms, Franz Joseph Gildehaus, Christoph J. Auernhammer, Christine Spitzweg, Mathias J. Zacherl, and et al. 2025. "Comparison of the Hematotoxicity of PRRT with Lutathera® and Locally Manufactured 177Lu-HA-DOTATATE in Patients with Neuroendocrine Tumors and the Impact of Different Application Intervals" Cancers 17, no. 9: 1423. https://doi.org/10.3390/cancers17091423
APA StyleHofmann, M., Kunte, S. C., Unterrainer, M., Delker, A., Holzgreve, A., Toms, J., Gildehaus, F. J., Auernhammer, C. J., Spitzweg, C., Zacherl, M. J., Ilhan, H., Rübenthaler, J., Beyer, L., & Unterrainer, L. M. (2025). Comparison of the Hematotoxicity of PRRT with Lutathera® and Locally Manufactured 177Lu-HA-DOTATATE in Patients with Neuroendocrine Tumors and the Impact of Different Application Intervals. Cancers, 17(9), 1423. https://doi.org/10.3390/cancers17091423