Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors
- 2.3k Downloads
Peptide receptor radionuclide therapy (PRRT) with 90Y and 177Lu provides objective responses in neuroendocrine tumours, and is well tolerated with moderate toxicity. We aimed to identify clinical parameters predictive of long-term renal and haematological toxicity (myelodysplastic syndrome and acute leukaemia).
Of 807 patients studied at IEO-Milan (1997–2013), 793 (98 %) received 177Lu (278, 34.4 %), 90Y (358, 44.4 %) or 177Lu and 90Y combined (157. 19.5 %), and 14 (2 %) received combinations of PRRT and other agents. Follow-up was 30 months (1–180 months). The parameters evaluated included renal risk factors, bone marrow toxicity and PRRT features. Data analysis included multiple regression, random forest feature selection, and recursive partitioning and regression trees.
Treatment with 90Y and 90Y + 177Lu was more likely to result in nephrotoxicity than treatment with 177Lu alone (33.6 %, 25.5 % and 13.4 % of patients, respectively; p < 0.0001). Nephrotoxicity (any grade), transient and persistent, occurred in 279 patients (34.6 %) and was severe (grade 3 + 4) in 12 (1.5 %). In only 20–27 % of any nephrotoxicity was the disease modelled by risk factors and codependent associations (p < 0.0001). Hypertension and haemoglobin toxicity were the most relevant factors. Persistent toxicity occurred in 197 patients (24.3 %). In only 22–34 % of affected patients was the disease modelled by the clinical data (p < 0.0001). Hypertension (regression coefficient 0.14, p < 0.0001) and haemoglobin toxicity (regression coefficient 0.21, p < 0.0001) were pertinent factors. Persistent toxicity was associated with shorter PRRT duration from the first to the last cycle (mean 387 vs. 658 days, p < 0.004). Myelodysplastic syndrome occurred in 2.35 % of patients (modelled by the clinical data in 30 %, p < 0.0001). Platelet toxicity grade (2.05 ± 1.2 vs. 0.58 ± 0.8, p < 0.0001) and longer PRRT duration (22.6 ± 24 vs. 15.5 ± 9 months, p = 0.01) were relevant. Acute leukaemia occurred in 1.1 % of patients (modelled by the clinical data in 18 %, p < 0.0001).
Identified risk factors provide a limited (<30 %) risk estimate even with target tissue dosimetry. These data strongly suggest the existence of unidentified individual susceptibilities to radiation-associated disease.
KeywordsPRRT NET Bone marrow toxicity Nephrotoxicity Decision tree analysis
Conflicts of interest
G.P. is consultant for AAA. D.J.K. and E.P.K. are shareholders of AAA and steering committee members of AAA's NETTER-1 study. The other authors declare no conflicts of interest.
- 4.Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol. 2011;29:2416–23. doi: 10.1200/jco.2010.33.7873.PubMedCrossRefGoogle Scholar
- 13.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. doi: 10.1007/s00259-008-0778-1.PubMedCrossRefGoogle Scholar
- 16.Dottorini ME, Salvatori M. Is radioiodine treatment for thyroid cancer a risk factor for second primary malignancies? Clin Transl Imaging. 2013;1:205–16. doi: 10.1007/s40336-013-0022-2.
- 18.Therneau T, Atkinson B, Ripley B. rpart: Recursive partitioning and regression times. 2014. http://cran.r-project.org/package=rpart/index.html.
- 20.Paganelli G, Sansovini M, Ambrosetti A, Severi S, Monti M, Scarpi E, et al. 177Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study. Eur J Nucl Med Mol Imaging. 2014. doi: 10.1007/s00259-014-2735-5.
- 27.Walrand S, Barone R, Pauwels S, Jamar F. Experimental facts supporting a red marrow uptake due to radiometal transchelation in 90Y-DOTATOC therapy and relationship to the decrease of platelet counts. Eur J Nucl Med Mol Imaging. 2011;38:1270–80. doi: 10.1007/s00259-011-1744-x.PubMedCrossRefGoogle Scholar