Skip to main content
SpringerLink
Log in

Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

In this phase II study we investigated the safety and efficacy of combination capecitabine and 177Lu-octreotate for the treatment of disseminated, progressive, unresectable neuroendocrine tumours (NETs).

Methods

Enrolled in the study were 33 patients with biopsy-proven NETs, positive 111In-octreotide scintigraphy and progressive disease measurable by CT/MRI who were to receive four cycles of 7.8 GBq 177Lu-octreotate 8-weekly, with 14 days of 1,650 mg/m2 capecitabine per day.

Results

Of the 33 patients, 25 completed four cycles. Minimal transient myelosuppression at 3–4 weeks caused grade 3 thrombocytopenia in one patient but no neutropenia. Nephrotoxicity was absent. Critical organ radiation dosimetry provided median estimates of the dose per cycle to the kidneys of 2.4 Gy and to the liver of 4.8 Gy, and showed cumulative doses all below toxic thresholds. Objective response rates (ORR) were 24% partial response (PR), 70% stable disease (SD) and 6% progressive disease. Median progression-free survival and median overall survival had not been reached at a median follow-up of 16 months (range 5–33 months). Survival at 1 and 2 years was 91% (95% CI 75–98%) and 88% (95% CI 71–96%), respectively.

Conclusion

The addition of capecitabine radiosensitizing chemotherapy does not increase the minimal toxicity of 177Lu-octreotate radiopeptide therapy and led to an ORR of 24% PR and 70% minor response or SD in patients with progressive metastatic NETs. Tumour control and stabilization of disease was obtained in 94% of these patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Modlin IM, Latich I, Kidd M, Zikusoka M, Eick G. Therapeutic options for gastrointestinal carcinoids. Clin Gastroenterol Hepatol 2006;4:526–47.

    Article  CAS  PubMed  Google Scholar 

  2. Waser B, Tamma ML, Cescato R, Maecke HR, Reubi JC. Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target tissues. J Nucl Med 2009;50:936–41.

    Article  CAS  PubMed  Google Scholar 

  3. Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27:4656–63.

    Article  CAS  PubMed  Google Scholar 

  4. De Jong M, Valkema R, Jamar F, Kvols LK, Kwekkeboom DJ, Breeman WA, et al. Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings. Semin Nucl Med 2002;32:133–40.

    Article  PubMed  Google Scholar 

  5. Reubi JC, Schar JC, Waser B, Wenger S, Heppeler A, Schmitt JS, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 2000;27:273–82.

    Article  CAS  PubMed  Google Scholar 

  6. Kong G, Johnston V, Ramdave S, Lau E, Rischin D, Hicks RJ. High-administered activity In-111 octreotide therapy with concomitant radiosensitizing 5FU chemotherapy for treatment of neuroendocrine tumors: preliminary experience. Cancer Biother Radiopharm 2009;24:527–33.

    Article  CAS  PubMed  Google Scholar 

  7. Kwekkeboom DJ, Mueller-Brand J, Paganelli G, Anthony LB, Pauwels S, Kvols LK, et al. Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs. J Nucl Med 2005;46 Suppl 1:S62–6.

    Google Scholar 

  8. Cwikla JB, Sankowski A, Seklecka N, Buscombe JR, Nasierowska-Guttmejer A, Jeziorski KG, et al. Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study. Ann Oncol 2010;21:787–94.

    Article  CAS  PubMed  Google Scholar 

  9. Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008;26:2124–30.

    Article  CAS  PubMed  Google Scholar 

  10. Kvols LK. Radiation sensitizers: a selective review of molecules targeting DNA and non-DNA targets. J Nucl Med 2005;46 Suppl 1:S187–90.

    Google Scholar 

  11. Glynne-Jones R, Dunst J, Sebag-Montefiore D. The integration of oral capecitabine into chemoradiation regimens for locally advanced rectal cancer: how successful have we been? Ann Oncol 2006;17:361–71.

    Article  CAS  PubMed  Google Scholar 

  12. Wong JY, Shibata S, Williams LE, Kwok CS, Liu A, Chu DZ, et al. A phase I trial of 90Y-anti-carcinoembryonic antigen chimeric T84.66 radioimmunotherapy with 5-fluorouracil in patients with metastatic colorectal cancer. Clin Cancer Res 2003;9:5842–52.

    CAS  PubMed  Google Scholar 

  13. van Essen M, Krenning EP, Kam BL, de Herder WW, van Aken MO, Kwekkeboom DJ. Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2008;35:743–8.

    Article  PubMed  Google Scholar 

  14. Breeman WA, De Jong M, Visser TJ, Erion JL, Krenning EP. Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities. Eur J Nucl Med Mol Imaging 2003;30:917–20.

    Article  CAS  PubMed  Google Scholar 

  15. Bolch WE, Bouchet LG, Robertson JS, Wessels BW, Siegel JA, Howell RW, et al. MIRD pamphlet No. 17: the dosimetry of nonuniform activity distributions – radionuclide S values at the voxel level. Medical Internal Radiation Dose Committee. J Nucl Med 1999;40:S11–36.

    Google Scholar 

  16. McKay E. A software tool for specifying voxel models for dosimetry estimation. Cancer Biother Radiopharm 2003;18:379–92.

    Article  PubMed  Google Scholar 

  17. Chiavassa S, Aubineau-Laniece I, Bitar A, Lisbona A, Barbet J, Franck D, et al. Validation of a personalized dosimetric evaluation tool (Oedipe) for targeted radiotherapy based on the Monte Carlo MCNPX code. Phys Med Biol 2006;51:601–16.

    Article  CAS  PubMed  Google Scholar 

  18. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47.

    Article  CAS  PubMed  Google Scholar 

  19. Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998;17:857–72.

    Article  CAS  PubMed  Google Scholar 

  20. Wilson E. Probable inference, the law of succession, and statistical inference. J Am Stat Assoc 1927;22:209–12.

    Article  Google Scholar 

  21. Yao JC. Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma. Best Pract Res Clin Endocrinol Metab 2007;21:163–72.

    Article  CAS  PubMed  Google Scholar 

  22. Gustafsson BI, Kidd M, Modlin IM. Neuroendocrine tumors of the diffuse neuroendocrine system. Curr Opin Oncol 2008;20:1–12.

    Article  PubMed  Google Scholar 

  23. Bushnell DL Jr, O'Dorisio TM, O'Dorisio MS, Menda Y, Hicks RJ, Van Cutsem E, et al. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol 2010;28:1652–9.

    Article  CAS  PubMed  Google Scholar 

  24. Turner JH. Defining pharmacokinetics for individual patient dosimetry in routine radiopeptide and radioimmunotherapy of cancer: Australian experience. Curr Pharm Des 2009;15:966–82.

    Article  CAS  PubMed  Google Scholar 

  25. Brayshaw P, Claringbold P, Turner J. Lutetium-177 octreotate radiopeptide therapy of endocrine cancer: tumor and critical organ dosimetry. J Nucl Med 2009;50 Suppl 2:499.

    Google Scholar 

  26. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109–22.

    CAS  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. Sandström M, Garske U, Granberg D, Sundin A, Lundqvist H. Individualized dosimetry in patients undergoing therapy with 177Lu-DOTA-D-Phe1-Tyr3-octreotate. Eur J Nucl Med Mol Imaging 2010;37:212–25.

    Article  PubMed  Google Scholar 

  30. Stabin MG. MIRDOSE: personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 1996;37:538–46.

    CAS  PubMed  Google Scholar 

  31. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 2005;46:1023–7.

    PubMed  Google Scholar 

  32. Stabin MG, Konijnenberg MW. Re-evaluation of absorbed fractions for photons and electrons in spheres of various sizes. J Nucl Med 2000;41:149–60.

    CAS  PubMed  Google Scholar 

  33. Forrer F, Krenning EP, Kooij PP, Bernard BF, Konijnenberg M, Bakker WH, et al. Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate. Eur J Nucl Med Mol Imaging 2009;36:1138–46.

    Article  CAS  PubMed  Google Scholar 

  34. De Paoli A, Chiara S, Luppi G, Friso ML, Beretta GD, Del Prete S, et al. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol 2006;17:246–51.

    Article  PubMed  Google Scholar 

  35. Moertel CG, Hanley JA. Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials 1979;2:327–34.

    CAS  PubMed  Google Scholar 

  36. Paulson EK, McDermott VG, Keogan MT, DeLong DM, Frederick MG, Nelson RC. Carcinoid metastases to the liver: role of triple-phase helical CT. Radiology 1998;206:143–50.

    CAS  PubMed  Google Scholar 

  37. Strosberg J, Choi J, Gardner N, Kvols L. First-line treatment of metastatic pancreatic endocrine carcinomas with capecitabine and temozolomide. J Clin Oncol 2008;26(15S):4612.

    Google Scholar 

Download references

Acknowledgments

The kind personal donation of octreotate peptide by Professor Eric Krenning, Erasmus Medical Centre, Rotterdam, The Netherlands, is gratefully acknowledged. The authors also wish to thank Ms. Anna Chiam for clinical data management, Ms. Suet Mei Yu for statistical analysis and Ms. Jenny Lavin for preparation of the manuscript. The chromogranin A assays were kindly performed by Ms. Zoe Inman and Ms. Nikki Orridge. Clinical data management was funded by the WA Cancer and Palliative Care Network. This was a physician-sponsored study approved by the Human Research Ethics Committee of Fremantle Hospital and Health Service.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Oncology, Fremantle Hospital, Alma Street, Fremantle, WA, 6160, Australia

    Phillip G. Claringbold

  2. Department of Nuclear Medicine, Fremantle Hospital, The University of Western Australia, Alma Street, Fremantle, WA, 6160, Australia

    Paul A. Brayshaw & J. Harvey Turner

  3. Department of Radiology, Fremantle Hospital, Alma Street, Fremantle, WA, 6160, Australia

    Richard A. Price

Authors
  1. Phillip G. Claringbold
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul A. Brayshaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard A. Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Harvey Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Harvey Turner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Claringbold, P.G., Brayshaw, P.A., Price, R.A. et al. Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours. Eur J Nucl Med Mol Imaging 38, 302–311 (2011). https://doi.org/10.1007/s00259-010-1631-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-010-1631-x

Keywords

Search

Navigation