Hematological Toxicity of Combined ¹⁷⁷Lu-Octreotate Radiopeptide Chemotherapy of Gastroenteropancreatic Neuroendocrine Tumors in Long-Term Follow-Up

Abstract

Background: The combination of radiopeptide therapy [peptide receptor radionuclide therapy (PRRT)] with radiosensitizing chemotherapy of gastroenteropancreatic neuroendocrine tumors (GEP NETs) may improve efficacy, but has the potential to increase myelotoxicity. In a prospective clinical study of GEP NET patients treated with ¹⁷⁷Lu-octreotate PRRT in combination with capecitabine and temozolomide, as a prelude to a planned Australasian Gastro-Intestinal Trials Group (AGITG) international randomized controlled trial, we characterized the incidence and degree of hematological toxicity. Materials and Methods: Well-differentiated progressive metastatic GEP NETs in 65 patients were treated with 4 cycles of 7.8 GBq ¹⁷⁷Lu-octreotate, 1,650 mg/m² capecitabine (n = 28) and 1,500 mg/m² capecitabine with 200 mg/m² temozolomide (n = 37), and monitored for hematological toxicity over a 5-year period. Results: Short-term, self-limited hematological toxicity grade 3/4 comprised anemia in 1 patient (3.5%) in the 28 patient-cohort of patients treated with ¹⁷⁷Lu-octreotate and capecitabine. One of these patients (3.5%) later developed significant anemia and one developed thrombocytopenia (3.5%) over a median follow-up of 60 months (SD 20). The incidence of short-term grade 3/4 reversible myelosuppression in 37 patients after ¹⁷⁷Lu-octreotate/capecitabine/temozolomide was zero. Long- term follow-up for a median of 36 months (SD 11) showed significant thrombocytopenia in 2.7% and neutropenia in 2.7% of the patients and anemia in 10.8% of the patients (n = 4). The 3-year median hemoglobin and platelet and neutrophil counts trended downwards, but remained within normal ranges. Two patients in this cohort developed myelodysplastic syndrome. Conclusion: The modest reversible hematological toxicity of PRRT of GEP NETs is not significantly increased by the addition of radiosensitizing chemotherapy with capecitabine and temozolomide in combination with ¹⁷⁷Lu-octreotate, which has the potential to enhance the efficacy of radiopeptide therapy.

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.…”

“…In another study, about 65 patients receiving 177 Lu-octreoate combined with capecitabine (n = 28) or capecitabine and temozolomide (n = 37), no MDS/AML was reported in the former group, but two (5.4%) cases were reported in the latter group (Kesavan et al 2014). Temozolomide is an alkylating agent, further supporting our assumption that the risk of MDS/AML, very low with 177 Lu-octreotate PRRT alone and possibly 177 Lu-octreotate PRRT combined with nonalkylating chemotherapy, may be higher when 177 Lu-octreotate PRRT is combined with alkylating agents.…”

Modifying the Poor Prognosis Associated with 18F-FDG–Avid NET with Peptide Receptor Chemo-Radionuclide Therapy (PRCRT)

“…In these patients, it appears PRCRT is able to convert the disease from an aggressive to an indolent phenotype. PRCRT is remarkably well tolerated, as we and others have previously described (5,7,8). However, there is a risk of long-term toxicity.…”