Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of ¹⁷⁷Lu-DOTATATE PRRT

Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity. Material and methods: Our single-center retrospective study enrolled all patients treated with 177Lu-DOTATATE PRRT (1–4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (N = 41), or targeted agents (everolimus, sunitinib or both; N = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored. Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (N = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events. Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.背景：肽受体放射性核素治疗（Peptide receptor radionuclide therapy, PRRT）是针对生长抑素受体过表达神经内分泌肿瘤（Neuroendocrine Tumors, NETs）的成熟治疗方案。NETTER-1试验证实，相较于高剂量生长抑素类似物（Somatostatin Analogues, SSAs），该疗法可显著改善无进展生存期，且总生存期亦呈现出明显的获益趋势。本研究旨在探讨依维莫司（everolimus）与/或舒尼替尼（sunitinib）的预处理方案对肽受体放射性核素治疗所致亚急性血液毒性的影响。鉴于短期血液毒性与晚期血液毒性发生率升高存在关联，明确依维莫司/舒尼替尼预处理的临床影响具有重要的现实意义。 材料与方法：本研究为单中心回顾性研究，纳入2013年11月至2018年7月期间接受177Lu-DOTATATE肽受体放射性核素治疗的全部患者，治疗方案为1~4个周期、每周期7.4 GBq。根据预处理方案将患者分为两组：未接受靶向药物治疗组（N=41），以及接受靶向药物（依维莫司、舒尼替尼或二者联用）治疗组（N=41）。本研究的终点事件为亚急性血液毒性，以首次给药至末次给药后3个月内的血细胞计数低谷值作为评估依据，采用不良事件通用术语标准4.03版（CTCAE 4.03）进行分级。此外，本研究亦探讨了脾切除术对血液毒性的影响。 结果：本研究纳入的患者中，80%为原发性胃肠胰神经内分泌肿瘤。与未接受预处理的患者组相比，预处理组在血红蛋白（3/4级毒性：12% vs 22%）、白细胞（3/4级毒性：10% vs 7%）、中性粒细胞（3/4级毒性：5% vs 7%）、淋巴细胞（3/4级毒性：49% vs 37%）及血小板（3/4级毒性：15% vs 15%）的严重亚急性血液毒性发生率上均未呈现统计学显著性差异。进一步分析显示，在接受脾切除术的亚组患者（N=12）中，其总白细胞、淋巴细胞及血小板的毒性发生率显著更低。本研究存在一定局限性：其一，毒性易感性较高的患者未使用靶向药物可能引入偏倚；其二，本研究的患者规模与事件数均较为有限。 结论：在接受过依维莫司与/或舒尼替尼预处理的神经内分泌肿瘤患者队列中，本研究未证实依维莫司与/或舒尼替尼的预处理方案对177Lu-DOTATATE肽受体放射性核素治疗所致的亚急性血液毒性存在显著影响。