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Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: a simulation study

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Peptide receptor radionuclide therapy (PRRT) with 177Lu-octreotate is commonly administered at empiric, fixed amounts of injected radioactivity (IA). This results in highly variable absorbed doses to critical organs and suboptimal treatment of most patients. The primary aims of this study were to design a personalized PRRT (P-PRRT) protocol based on dosimetry, and to perform a simulation of this protocol in a retrospective cohort of patients with neuroendocrine tumours, in order to assess the potential of P-PRRT to safely increase the absorbed dose to the tumour during a four-cycle induction course.

Methods

Thirty-six patients underwent 122 fixed-IA 177Lu-octreotate PRRT cycles with quantitative SPECT/CT-based dosimetry. Twenty-two patients completed a four-cycle induction course (29.6 ± 2.4 GBq cumulative IA), with kidney, bone marrow and maximum tumour absorbed doses of 16.2 ± 5.5, 1.3 ± 0.8, and 114 ± 66 Gy, respectively. We simulated a P-PRRT regime in which the renal absorbed dose per IA was predicted by the body surface area and glomerular filtration rate for the first cycle, and by renal dosimetry of the previous cycle(s) for the following cycles. Personalized IA was adjusted at each cycle in order to reach the prescribed renal absorbed dose of 23 Gy over four cycles (with a 25-50% reduction when renal or bone marrow function was impaired). Simulated IA and absorbed doses were based on actual patient characteristics, laboratory values and absorbed doses per IA delivered at each cycle.

Results

In the P-PRRT regime, cumulative IA could have been increased to 43.7 ± 16.5 GBq over four induction cycles (10.9 ± 5.0 GBq per cycle), yielding cumulative kidney, bone marrow and maximum tumour absorbed doses of 21.5 ± 2.5, 1.63 ± 0.61, and 163.4 ± 85.9 Gy, respectively. This resulted in an average 1.48-fold increase in cumulative maximum tumour absorbed dose over empiric PRRT (range, 0.68–2.64-fold; P = 0.0013).

Conclusion

By standardizing the renal absorbed dose delivered during the induction course, P-PRRT has the potential to significantly increase tumour absorbed dose, thus to augment the therapeutic benefit while limiting toxicity.

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Acknowledgements

We thank Anna Celler, Ph.D. (University of British Columbia), her students, and Curtis Caldwell, Ph.D. (University of Toronto), for their ongoing collaboration on quantitative SPECT and dosimetry methods. We are grateful to the nurses and nuclear medicine technologists at the CHU de Québec who provided care for PRRT patients, as well as to Richard Poulin, Ph.D., for his help with the writing of this manuscript.

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Corresponding author

Correspondence to Jean-Mathieu Beauregard.

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Funding

J.M.B. is supported by a Clinical Research Scholar grant from the Fonds de recherche du Québec – Santé. M.D.P. is supported by a Merit Scholarship for Foreign Students from the Ministère de l’éducation et de l’enseignement supérieur du Québec, a Ph.D. scholarship for foreign students from the Quebec Bio-Imaging Network, and a Ph.D. scholarship from the Oncology Branch of the CHU de Québec Research Center (donated by the Harley Owners Group of Quebec City). This work was partly funded by Canadian Institutes of Health Research (CIHR) operating grant MOP-142233 to J.M.B.

Conflicts of interest

None.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Suppl. Fig. 1

Subacute bone marrow dose-toxicity relationships. No significant correlation was found between the absolute and relative white blood cell count (a and b; Spearman r = -0.06, P = 0.60 and r = -0.09, P = 0.44, respectively; n = 76), haemoglobin (c and d; Spearman r = -0.19, P = 0.11 and r = -0.21, P = 0.07, respectively; n = 76), neutrophil count (e and f; Spearman r = 0.07, P = 0.55 and r = 0.04, P = 0.72, respectively; n = 74) and lymphocyte count (g and h; Spearman r = 0.12, P = 0.30 and r = 0.02, P = 0.86, respectively; n = 74) variations and the per-cycle bone marrow absorbed dose (Gy) (DOCX 113 kb)

Suppl. Fig. 2

Chronic bone marrow dose-toxicity relationships (n = 19). No significant correlation was found between the absolute and relative white blood cell count (a and b; Pearson r = -0.03, P = 0.90 and Spearman r = -0.21, P = 0.38, respectively), haemoglobin (c and d; Pearson r = 0.11, P = 0.63 and r = 0.13, P = 0.61, respectively), platelet count (e and f; Spearman r = 0.18, P = 0.47 and Pearson r = 0.09, P = 0.70, respectively), neutrophil count (g and h; Pearson r = -0.04, P = 0.86 and r = -0.11, P = 0.64, respectively) and lymphocyte count (i and j; Spearman r = -0.17, P = 0.48 and Pearson r = -0.03, P = 0.91, respectively) variations and the cumulative bone marrow absorbed dose (Gy). + indicates patients (n = 5) who received maintenance cycles following response to the induction course (DOCX 546 kb)

Suppl. Fig. 3

Chronic renal dose-toxicity relationship (n = 19). No significant correlation was found between the absolute and relative estimated glomerular filtration rate (a and b; Pearson r = 008, P = 0.76 and r = 0.01, P = 0.98, respectively), creatinine (c and d; Pearson r = 0.13, P = 0.58 and r = 0.06, P = 0.80, respectively) and creatinine clearance estimated by the Cockcroft-Gault equation (e and f; Pearson r = 0.22, P = 0.36 and r = 0.31, P = 0.19, respectively) variations and the cumulative renal absorbed dose (Gy). + indicates patients (n = 5) who received maintenance cycles following response to the induction course (DOCX 339 kb)

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Del Prete, M., Buteau, FA. & Beauregard, JM. Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: a simulation study. Eur J Nucl Med Mol Imaging 44, 1490–1500 (2017). https://doi.org/10.1007/s00259-017-3688-2

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  • DOI: https://doi.org/10.1007/s00259-017-3688-2

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