. 2023 Oct 2;15(19):4836. doi: 10.3390/cancers15194836

Table 2.

Safety and monitoring considerations for ¹⁷⁷Lu-DOTATATE RLT in GEP-NETs.

Safety Considerations	Incidence (%)	Time Course	General RLT Monitoring Considerations	Individual Patient Considerations ^a
Acute Reactions
Neuroendocrine hormonal crisis (carcinoid crisis)	ERASMUS [10] <1 Systematic review [42] 1–10	Most commonly occurs at cycle 1 during or within a day of the infusion [10,42]	Signs and symptoms of tumor-related hormonal release should be monitored (e.g., flushing, diarrhea, hypotension, and bronchoconstriction) [10]	In cases of severe neuroendocrine hormonal crisis (carcinoid crisis), hospital admission for closer monitoring/management may be required
Adverse events during and after RLT
Grade ≥3 myelosuppression	NETTER-1 [11]	Transient in nature with resolution within 8 weeks for thrombocytopenia and neutropenia [7,11]; In NETTER-1, median time to platelet nadir was 5.1 weeks after the first dose and median time to platelet recovery was 2 months [10]	Baseline laboratory thresholds for RLT eligibility ^b: Hemoglobin >8 g/dL; White blood cell count >2000/mm³; Platelet count >70,000/mm³ (or 75,000/mm³ if using CTCAE grading criteria thresholds); Blood cell counts should be monitored after each RLT cycle [10]. The timing of blood testing varies in real-world practice, but every 4–6 weeks is reasonable to capture the nadir of blood counts; It has been recommended that blood tests be performed 1, 3, 6, and 12 months after RLT completion and then at least yearly thereafter if results have been normal [7]	The cause of cytopenia should be considered when assessing RLT eligibility. For example, if reduced platelet counts are due to splenic sequestration, the patient could still be a viable RLT candidate; Patients with abnormal blood tests should be monitored more closely (hematology consult, increased testing frequency) [7]
Thrombocytopenia	2
Anemia	0
Lymphopenia	9
Leukopenia	1
Neutropenia	1
Renal toxicity Grade ≥ 3 nephrotoxicity Grade ≥ 3 serum creatinine increase	NETTER-1 [11,43] 5 1	No therapy-related long-term renal failure in NETTER-1 [11,43] or ERASMUS [44]; at 5-year follow-up of NETTER-1, mean change from baseline for CrCL was similar between RLT and control groups [43]	Baseline laboratory thresholds for RLT eligibility: ^b eGFR < 50 mL/min/1.73 m² not a contraindication [9] eGFR < 30 mL/min/1.73 m² (use only in exceptional circumstances) [9]. Serum creatinine and CrCL should be monitored when patients are on RLT [10]; It has been recommended that serum creatinine/eGFR be assessed at 1, 3, 6, and 12 months after RLT completion and then at least yearly thereafter if results have been normal [7]	Risk factors for renal toxicity include hypertension, diabetes, and pre-existing RI [10,45]; Patients with mild or moderate RI should have more frequent renal assessments [10]
Hepatotoxicity Hepatic tumor hemorrhage, edema, or necrosis	ERASMUS [44] <1 [10]	ERASMUS [44] No therapy-related long-term hepatic failure	Laboratory thresholds for RLT eligibility ^b: Total bilirubin ≤3 × ULN; Serum albumin >3.0 g/dL During RLT, transaminases, bilirubin, and serum albumin should be monitored [10]; It has been recommended that liver panels be assessed at 1, 3, 6, and 12 months after RLT completion and then at least yearly thereafter if results have been normal [7]	Anatomic imaging can help determine if elevated bilirubin is due to biliary obstruction rather than RLT-induced toxicity; Hepatotoxicity may be more common in patients with extensive hepatic metastases [46] or prior SIRT [47,48]
Long-term safety considerations
MDS and leukemia	NETTER-1 [11,43] MDS: 1.8 Leukemia: 0 ERASMUS [44] MDS: 1.5 Leukemia: 0.7 Systematic review [49] RLT-related myeloid neoplasm: 2.61	In NETTER-1, 2 cases of MDS occurred at 8 and 14 months after first RLT dose—no new cases of MDS or leukemia were reported during long-term follow-up [43]; in ERASMUS, acute leukemia and MDS occurred after median follow-up durations of 55 and 28 months, respectively [44]	No robust pre-emptive monitoring options	Risk factors for MDS/leukemia include prior chemotherapy and radiotherapy (including SIRT) [50]; Patients with persistent cytopenias merit closer monitoring (hematology consult; increased testing frequency) [7]

^a In general, frequency of monitoring should be tailored to the risk of progressive disease (tumor grade and bulk), functional status, and concern for post-RLT adverse events [7]. ^b Laboratory thresholds are those recommended by the NANETS/SNMMI Procedure Standard for RLT with ¹⁷⁷Lu-DOTATATE; these guidelines state that the thresholds should be considered as general RLT eligibility criteria [7]. ¹⁷⁷Lu = lutetium-177; CrCL = creatinine clearance; CTCAE = Common Terminology Criteria for Adverse Events; eGFR = estimated glomerular filtration rate; MDS = myelodysplastic syndrome; NANETS = North American Neuroendocrine Tumor Society; RI = renal impairment; RLT = radioligand therapy; SIRT = selective internal radiation therapy; SNMMI = Society of Nuclear Medicine and Molecular Imaging; ULN = upper limit of normal.