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Extended peptide receptor radionuclide therapy: evaluating nephrotoxicity and therapeutic effectiveness in neuroendocrine tumor patients receiving more than four treatment cycles

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Abstract

Purpose

Currently, the most used peptide receptor radionuclide therapy (PRRT) regimen for neuroendocrine tumors comprises 4 treatment cycles, and there is not enough large-scale data to support the safety of more individualized extended PRRT. This study aims to evaluate the therapeutic effectiveness and potential nephrotoxicity related to PRRT using more than four treatment cycles.

Methods

In this retrospective analysis, we included patients who had received at least four PRRT cycles and had available follow-up data. We analyzed renal function indicators before and after multiple treatments, comparing nephrotoxicity in patients receiving four cycles (“standard”) with those receiving more than four (“extended treatment”). Nephrotoxicity was assessed via creatinine levels and CTCAE creatinine grades. Treatment effectiveness was gauged using Kaplan–Meier survival analysis, focusing on overall survival and disease-specific survival (DSS). Statistical analyses were performed using SPSS version 26 (IBM), R 4.2.3, and GraphPad Prism 9.0.0. Statistical significance was defined as a P-value of less than 0.05.

Results

Our study cohort consisted of 281 patients in the standard group and 356 in the extended treatment group. No significant differences in baseline characteristics or renal function were noted between the two groups pre-treatment. Mean post-treatment creatinine levels did not significantly differ between the standard (89.30 ± 51.19 μmol/L) and extended treatment groups (93.20 ± 55.98 μmol/L; P = 0.364). Similarly, there was no statistical significance between the CTCAE creatinine grades of the two groups (P = 0.448). Adverse renal events were observed in 0.4% of patients in the standard group and 1.1% in the extended treatment group. After a median follow-up time of 88.3 months, we found that median overall survival was significantly higher in the extended treatment group (72.8 months) compared to the standard treatment group (52.8 months). A Cox regression analysis further supported these findings, indicating a better prognosis for the extended treatment group in terms of overall survival (HR: 0.580, P < 0.001) and DSS (HR: 0.599, P < 0.001).

Conclusion

Our findings suggest that extending PRRT treatment beyond the standard four cycles may be a safe and effective therapeutic strategy for NET patients. This approach could be particularly beneficial for patients experiencing disease recurrence or progression following standard treatment.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding authors upon reasonable request.

References

  1. Sowa-Staszczak A, Pach D, Chrzan R, Trofimiuk M, Stefańska A, Tomaszuk M, et al. Peptide receptor radionuclide therapy as a potential tool for neoadjuvant therapy in patients with inoperable neuroendocrine tumours (NETs). Eur J Nucl Med Mol Imaging. 2011;38:1669–74. https://doi.org/10.1007/s00259-011-1835-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bodei L, Cremonesi M, Ferrari M, Pacifici M, Grana CM, Bartolomei M, et al. 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;35:1847–56. https://doi.org/10.1007/s00259-008-0778-1.

    Article  CAS  PubMed  Google Scholar 

  3. Vegt E, de Jong M, Wetzels JF, Masereeuw R, Melis M, Oyen WJ, et al. Renal toxicity of radiolabeled peptides and antibody fragments: mechanisms, impact on radionuclide therapy, and strategies for prevention. J Nucl Med. 2010;51:1049–58. https://doi.org/10.2967/jnumed.110.075101.

    Article  CAS  PubMed  Google Scholar 

  4. Alsadik S, Gnanasegaran G, Chen L, Quigley AM, Mandair D, Toumpanakis C, et al. Single centre retrospective review of outcome of (177) Lu-DOTATATE peptide receptor radionuclide therapy in the treatment of progressive metastatic neuroendocrine tumours: Survival, toxicity, and prognostic factors. J Neuroendocrinol. 2022;34: e13210. https://doi.org/10.1111/jne.13210.

    Article  CAS  PubMed  Google Scholar 

  5. Severi S, Sansovini M, Ianniello A, Bodei L, Nicolini S, Ibrahim T, et al. Feasibility and utility of re-treatment with (177)Lu-DOTATATE in GEP-NENs relapsed after treatment with (90)Y-DOTATOC. Eur J Nucl Med Mol Imaging. 2015;42:1955–63. https://doi.org/10.1007/s00259-015-3105-7.

    Article  CAS  PubMed  Google Scholar 

  6. Virgolini I. Peptide receptor radionuclide therapy (PRRT): clinical significance of re-treatment? Eur J Nucl Med Mol Imaging. 2015;42:1949–54. https://doi.org/10.1007/s00259-015-3153-z.

    Article  PubMed  Google Scholar 

  7. Rolleman EJ, Valkema R, de Jong M, Kooij PP, Krenning EP. Safe and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine. Eur J Nucl Med Mol Imaging. 2003;30:9–15. https://doi.org/10.1007/s00259-002-0982-3.

    Article  CAS  PubMed  Google Scholar 

  8. Nilica B, Svirydenka A, Fritz J, Bayerschmidt S, Kroiss A, Gruber L, et al. Nephrotoxicity and hematotoxicity one year after four cycles of peptide receptor radionuclide therapy (PRRT) and its impact on future treatment planning - A retrospective analysis. Rev Esp Med Nucl Imagen Mol (Engl Ed). 2022;41:138–45. https://doi.org/10.1016/j.remnie.2021.04.007.

    Article  PubMed  Google Scholar 

  9. Zandee WT, Brabander T, Blažević A, Kam BLR, Teunissen JJM, Feelders RA, et al. Symptomatic and Radiological Response to 177Lu-DOTATATE for the Treatment of Functioning Pancreatic Neuroendocrine Tumors. J Clin Endocrinol Metab. 2019;104:1336–44. https://doi.org/10.1210/jc.2018-01991.

    Article  PubMed  Google Scholar 

  10. Zandee WT, Feelders RA, Smit Duijzentkunst DA, Hofland J, Metselaar RM, Oldenburg RA, et al. Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using 177Lu-DOTATATE. Eur J Endocrinol. 2019;181:45–53. https://doi.org/10.1530/eje-18-0901.

    Article  CAS  PubMed  Google Scholar 

  11. Sitani K, Parghane R, Talole S, Basu S. The efficacy, toxicity and survival of salvage retreatment PRRT with (177)Lu-DOTATATE in patients with progressive NET following initial course of PRRT. Br J Radiol. 2022;95:20210896. https://doi.org/10.1259/bjr.20210896.

    Article  PubMed  Google Scholar 

  12. Rudisile S, Gosewisch A, Wenter V, Unterrainer M, Böning G, Gildehaus FJ, 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;19:788. https://doi.org/10.1186/s12885-019-6000-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schuchardt C, Kulkarni HR, Prasad V, Zachert C, Müller D, Baum RP. The Bad Berka dose protocol: comparative results of dosimetry in peptide receptor radionuclide therapy using (177)Lu-DOTATATE, (177)Lu-DOTANOC, and (177)Lu-DOTATOC. Recent Results Cancer Res. 2013;194:519–36. https://doi.org/10.1007/978-3-642-27994-2_30.

    Article  CAS  PubMed  Google Scholar 

  14. Wehrmann C, Senftleben S, Zachert C, Müller D, Baum RP. Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu DOTA-TATE and 177Lu DOTA-NOC. Cancer Biother Radiopharm. 2007;22:406–16. https://doi.org/10.1089/cbr.2006.325.

    Article  CAS  PubMed  Google Scholar 

  15. Baum RP, Kulkarni HR. THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy - The Bad Berka Experience. Theranostics. 2012;2:437–47. https://doi.org/10.7150/thno.3645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yordanova A, Mayer K, Brossart P, Gonzalez-Carmona MA, Strassburg CP, Essler M, et al. Safety of multiple repeated cycles of (177)Lu-octreotate in patients with recurrent neuroendocrine tumour. Eur J Nucl Med Mol Imaging. 2017;44:1207–14. https://doi.org/10.1007/s00259-017-3652-1.

    Article  CAS  PubMed  Google Scholar 

  17. Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, 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;23:4617–24. https://doi.org/10.1158/1078-0432.Ccr-16-2743.

    Article  CAS  PubMed  Google Scholar 

  18. Tierney JF, Poirier J, Chivukula S, Pappas SG, Hertl M, Schadde E, et al. Primary Tumor Site Affects Survival in Patients with Gastroenteropancreatic and Neuroendocrine Liver Metastases. Int J Endocrinol. 2019;2019:9871319. https://doi.org/10.1155/2019/9871319.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, Díaz-Pérez JA, Martínez Del Prado MP, Alonso Orduña V, et al. Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol. 2010;21:1794–803. https://doi.org/10.1093/annonc/mdq022.

    Article  CAS  PubMed  Google Scholar 

  20. Menda Y, Madsen MT, O’Dorisio TM, Sunderland JJ, Watkins GL, Dillon JS, et al. (90)Y-DOTATOC Dosimetry-Based Personalized Peptide Receptor Radionuclide Therapy. J Nucl Med. 2018;59:1692–8. https://doi.org/10.2967/jnumed.117.202903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M, 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;42:5–19. https://doi.org/10.1007/s00259-014-2893-5.

    Article  CAS  PubMed  Google Scholar 

  22. Seregni E, Maccauro M, Chiesa C, Mariani L, Pascali C, Mazzaferro V, et al. Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy. Eur J Nucl Med Mol Imaging. 2014;41:223–30. https://doi.org/10.1007/s00259-013-2578-5.

    Article  CAS  PubMed  Google Scholar 

  23. Kunikowska J, Pawlak D, Bak MI, Kos-Kudla B, Mikolajczak R, Krolicki L. Long-term results and tolerability of tandem peptide receptor radionuclide therapy with (90)Y/(177)Lu-DOTATATE in neuroendocrine tumors with respect to the primary location: a 10-year study. Ann Nucl Med. 2017;31:347–56. https://doi.org/10.1007/s12149-017-1163-6.

    Article  CAS  PubMed  Google Scholar 

  24. Kunikowska J, Królicki L, Hubalewska-Dydejczyk A, Mikołajczak R, Sowa-Staszczak A, Pawlak D. Clinical results of radionuclide therapy of neuroendocrine tumours with 90Y-DOTATATE and tandem 90Y/177Lu-DOTATATE: which is a better therapy option? Eur J Nucl Med Mol Imaging. 2011;38:1788–97. https://doi.org/10.1007/s00259-011-1833-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ferdinandus J, Fendler WP, Lueckerath K, Berliner C, Kurzidem S, Hadaschik E, et al. Response to Combined Peptide Receptor Radionuclide Therapy and Checkpoint Immunotherapy with Ipilimumab Plus Nivolumab in Metastatic Merkel Cell Carcinoma. J Nucl Med. 2022;63:396–8. https://doi.org/10.2967/jnumed.121.262344.

    Article  PubMed  Google Scholar 

  26. Yordanova A, Ahrens H, Feldmann G, Brossart P, Gaertner FC, Fottner C, et al. Peptide receptor radionuclide therapy combined with chemotherapy in patients with neuroendocrine tumors. Clin Nucl Med. 2019;44:e329–35. https://doi.org/10.1097/rlu.0000000000002532.

    Article  PubMed  Google Scholar 

  27. Shi M, Jakobsson V, Greifenstein L, Khong PL, Chen X, Baum RP, et al. Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists. Front Med (Lausanne). 2022;9:1034315. https://doi.org/10.3389/fmed.2022.1034315.

    Article  PubMed  Google Scholar 

  28. Liu Q, Zang J, Sui H, Ren J, Guo H, Wang H, et al. Peptide Receptor Radionuclide Therapy of Late-Stage Neuroendocrine Tumor Patients with Multiple Cycles of (177)Lu-DOTA-EB-TATE. J Nucl Med. 2021;62:386–92. https://doi.org/10.2967/jnumed.120.248658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu Q, Cheng Y, Zang J, Sui H, Wang H, Jacobson O, et al. Dose escalation of an Evans blue-modified radiolabeled somatostatin analog (177)Lu-DOTA-EB-TATE in the treatment of metastatic neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2020;47:947–57. https://doi.org/10.1007/s00259-019-04530-1.

    Article  CAS  PubMed  Google Scholar 

  30. Jiang Y, Liu Q, Wang G, Zhang J, Zhu Z, Chen X. Evaluation of Safety, Biodistribution, and Dosimetry of a Long-Acting Radiolabeled Somatostatin Analog 177 Lu-DOTA-EB-TATE With and Without Amino Acid Infusion. Clin Nucl Med. 2023;48:e289–93. https://doi.org/10.1097/RLU.0000000000004642.

    Article  PubMed  Google Scholar 

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Funding

This work was supported by the National University of Singapore (NUHSRO/2021/097/Startup/13; NUHSRO/2020/133/Startup/08; NUHSRO/2023/008/NUSMed/TCE/LOA, NUHSRO/2021/034/TRP/09/Nanomedicine), National Medical Research Council (MOH-001334-00, MOH-001388-00, MOH-001254-01, CG21APR1005), Singapore Ministry of Education (MOE-000387-00), Singapore Ministry of Education (FY2022) Tier 1 Grant (NUHSRO/2022/093/T1/Seed-Sep/06), and the International Centers for Precision Oncology (ICPO) Foundation.

Author information

Author notes

  1. Richard P. Baum and **n Fan contributed equally to this work.

Authors and Affiliations

  1. Center for Advanced Radiomolecular Precision Oncology, CURANOSTICUM Wiesbaden-Frankfurt, Wiesbaden, Germany

    Richard P. Baum

  2. Theranostics Center for Molecular Radiotherapy and Precision Oncology, ENETS Center of Excellence, Zentralklinik Bad Berka, Bad Berka, Germany

    Richard P. Baum & Christiane Schuchardt

  3. Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    **n Fan, Vivianne Jakobsson, **aoyuan Chen & **g**g Zhang

  4. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    **n Fan, Vivianne Jakobsson, **aoyuan Chen & **g**g Zhang

  5. Department of Nuclear Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China

    **n Fan & Fei Yu

  6. Institute of Nuclear Medicine, Tongji University School of Medicine, Shanghai, China

    **n Fan & Fei Yu

  7. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Vivianne Jakobsson, **aoyuan Chen & **g**g Zhang

  8. Department of Surgery, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore

    **aoyuan Chen

  9. Department of Chemical and Biomolecular Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore

    **aoyuan Chen

  10. Department of Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore

    **aoyuan Chen

  11. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore

    **aoyuan Chen

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  1. Richard P. Baum
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Corresponding authors

Correspondence to Fei Yu or **g**g Zhang.

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Baum, R.P., Fan, X., Jakobsson, V. et al. Extended peptide receptor radionuclide therapy: evaluating nephrotoxicity and therapeutic effectiveness in neuroendocrine tumor patients receiving more than four treatment cycles. Eur J Nucl Med Mol Imaging 51, 1136–1146 (2024). https://doi.org/10.1007/s00259-023-06544-2

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