Long-Term Hematotoxicity After Peptide Receptor Radionuclide Therapy with ¹⁷⁷Lu-Octreotate

Abstract

Myelosuppression may be the dose-limiting toxicity in peptide receptor radionuclide therapy (PRRT). The aim of this study was to investigate the incidence, severity, and reversibility of long-term hematotoxicity in a large cohort of patient undergoing PRRT with 177 Lu-octreotate for metastatic neuroendocrine tumors. The impact of potential risk factors, including initial cytopenia, advanced bone metastatic disease, previous chemotherapy, and cumulative administered activity, and the protective effects of splenectomy were of particular interest. Methods: A total of 632 PRRT courses were performed in 203 patients with metastatic neuroendocrine tumors. A mean activity of 7.9 GBq of 177 Lu-octreotate was administered per treatment cycle, with a goal of 4 courses at standard intervals of 3 mo. Hematologic parameters were determined before each treatment course, at 2-to 4-wk intervals between the courses, 8-12 wk after the last course of PRRT, and at 3-month intervals for further follow-up. Toxicity was recorded with Common Terminology Criteria for Adverse Events (version 3.0). Results: Myelodysplastic syndrome as a delayed adverse event was documented in 3 patients (1.4%). Relevant but reversible hematotoxicity (grade 3 or 4) occurred in 23 patients (11.3%) and 29 administrations (4.6%), with leukopenia in 2.7% and thrombocytopenia in 1.7%. The mean time to blood count recovery was 12 mo after the termination of PRRT (range, 3-22 mo). The only preexisting factor that contributed to hematotoxicity was initial cytopenia (P , 0.001). A high level of cumulative administered activity (.29.6 GBq) was associated with relevant leukopenia (P , 0.001). None of the patients with a history of splenectomy developed grade 3 or 4 hematotoxicity, and splenectomy was inversely associated with the incidence and degree of leukopenia (P 5 0.02) and thrombocytopenia (P 5 0.03) Conclusion: PRRT-induced myelosuppression is almost invariably reversible and rarely requires clinical measures. Administered activity and initial cytopenia are the only factors contributing to myelosuppression, whereas splenectomy may exert a protective effect. Pept ide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a highly effective systemic treatment in patients with metastatic gastroenteropancreatic neuroendocrine tumors (NETs) (1-9). Bone marrow suppression is regarded as one of the most serious side effects after PRRT (10-13). Because of the lower energy and the shorter tissue penetration of the emitted b particles, treatment with 177 Lu-labeled peptides may result in a lower level of overall toxicity than PRRT with 90 Y-labeled peptides (14). However, there are only limited data regarding hematotoxicity after PRRT with 177 Lu-octreotate and contributing risk factors (2,15,16).The aim of this retrospective study was to investigate the incidence, severity, and reversibility of myelosuppression in a large cohort of patients with metastatic gastroenteropancreatic NETs treated with 177 Lu-octreotate. The impact of potential risk f...

High risk of myelodysplastic syndrome and acute myeloid leukemia after 177Lu-octreotate PRRT in NET patients heavily pretreated with alkylating chemotherapy

“…The duration of follow-up in our series (3.1 years) cannot explain differences of MDS/AML rates compared with other studies: indeed, although three studies had shorter follow-up (1.6, 1.9, and 2.6 years) (Kwekkeboom et al 2008, Imhof et al 2011, Sabet et al 2013, two other studies had similar or longer follow-up (3.0 and 4.2 years) (Kesavan et al 2014, Bodei et al 2015. Because of the known leukemogenic role of alkylating agents, we cannot exclude that MDS/AML in our series was a direct consequence of prior chemotherapy.…”

“…The high rate of MDS or AML (20%) we report in this limited series of 20 nonresectable NETs treated with 177 Lu-PPRT after heavy pretreatment with chemotherapy is therefore much higher than in large published series of PRRT (Kwekkeboom et al 2008, Imhof et al 2011, Sabet et al 2013, Kesavan et al 2014, Bodei et al 2015. This higher rate may be due to the fact that most of our patients had received chemotherapy and alkylating agents prior to PPRT, compared to previously published series of PPRT in metastatic NETs, where less than onethird of the patients had received chemotherapy before PRRT.…”

“…PRRT is generally well tolerated, short-term side effects include mild fatigue, hematological and renal toxicity. Regarding longer term hematological side effects, myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) was reported in 0.2-5.4% of the patients in large series (Kwekkeboom et al 2008, Imhof et al 2011, Sabet et al 2013, Kesavan et al 2014, Bodei et al 2015. Here, we report a much higher occurrence of MDS or AML in a single-center experience in patients treated with 177 Lutetium-octreotate at late disease stage, after alkylating-based chemotherapy.…”

Whither peptide receptor radionuclide therapy for neuroendocrine tumors: an Einsteinian view of the facts and myths

“…Severe, grade 3 or 4 hematological toxicity occurs in less than 15 % [26,27,37,38]. A highgrade potentially life-threatening bone marrow toxicity (myelodysplasia) is reported in up to 2 % [39][40][41]. An association with prior chemotherapy or radiotherapy has been implicated and may represent a confounding factor in assigning a causal relationship [31].…”

How smart is peptide receptor radionuclide therapy of neuroendocrine tumors especially in the salvage setting? The clinician’s perspective

“…Similarly severe hematotoxicity such as myelodysplastic syndrome (MDS) which has an occurrence ranging from 1 % to 2 % can be life-threatening [6][7][8][9]. Based upon dosimetry data and experience accumulated over the past 15 years, several patient-related coexisting risk factors compounding the toxicity of PRRT have been identified.…”