Subacute haematotoxicity after PRRT with 177Lu-DOTA-octreotate: prognostic factors, incidence and course

Abstract

PurposeIn peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from 131I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with 177Lu-DOTA0-Tyr3-octreotate (177Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit.MethodsThe incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined.ResultsHaematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0 × 109/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67 ± 7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq 177Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients.ConclusionThe incidence of subacute haematological toxicity after PRRT with 177Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from 131I, seems not to be valid for PRRT with 177Lu-DOTATATE.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-015-3193-4) contains supplementary material, which is available to authorized users.

Improved safety and efficacy of 213Bi-DOTATATE-targeted alpha therapy of somatostatin receptor-expressing neuroendocrine tumors in mice pre-treated with l-lysine

“…Weight loss in animals is often an indicator of toxicity, and the most radiosensitive organs for PRRT are the bone marrow and kidney [8, 28, 29]. In this study, we observed severe weight loss in 67% of animals exposed to high-dose 213 Bi-DOTATATE (cumulative 33.1 ± 3.7 MBq), within 2 weeks after treatment, indicating acute toxicity.…”

“…The mass of injected peptide influences the pharmacokinetics (PK) and absorbed doses in organs and tumors [6]. Therefore, the mass of injected peptide should be optimized to deliver efficacious tumor doses while avoiding toxic absorbed dose to organs, especially to the dose-limiting organs the kidneys and bone marrow [7, 8]. …”

Somatostatin Receptor 2–Targeting Compounds

“…In large trials, grade 3 or 4 hematologic toxicity has been reported in 3%-14% of the patients (26)(27)(28). Long-term myelotoxicity in the form of myelodysplastic syndrome or acute leukemia is a rare and severe adverse event associated with PRRT, occurring in 1%-2% of patients (29).…”

Clinical History of the Theranostic Radionuclide Approach to Neuroendocrine Tumors and Other Types of Cancer: Historical Review Based on an Interview of Eric P. Krenning by Rachel Levine

“…In addition, overall, there was no observed dose-response effect on serious (permanent) bone marrow toxicity, and it was believed to be unlikely that the widely used bone marrow limit of 2 Gy had any validity with regard to this radioligand (43). Finally, this experience also demonstrated that PRRT with [ 177 Lu-DOTA,Tyr 3 ]octreotate, administered in conjunction with appropriate amounts of amino acids for kidney protection, had virtually no renal toxicity (44).…”