Posology for ¹⁷⁷Lu-DOTATATE Therapy in Neuroendocrine Tumor

Abstract

Approval of ¹⁷⁷Lu-DOTATATE for the treatment of neuroendocrine tumors (NETs) requires monitoring for therapeutic efficacy and safety. A retrospective review was conducted on 173 patients who received ¹⁷⁷Lu-DOTATATE at the University of Michigan to identify if posology changes would improve therapy tolerance and completion. Patients were followed up to 3 years following their last cycle of treatment to determine long-term adverse events. Dose reduction (from 7.4 GBq to 3.7 GBq) was used in 13 patients, and cycle delay (8±1 wk to >16-week gap) was used in 36 patients, leading to 82% completion of 4 cycles of therapy. Dose reduction led to higher rates for completing all 4 cycles of therapy, whereas cycle delay led to worsened outcomes. Amino acid infusions led to limited adverse events with nausea, vomiting, and fatigue, even with antiemetic prophylaxis. Carcinoid crisis was observed in 1.2% of patients, which was similar to the findings in the NETTER-1 trial. Acute decline in neutrophils and platelets was observed; however, these blood values rebounded. A decline in renal function (4.3 mL/min/1.73 m² over 4 years compared with untreated patients) suggests a potential long-term risk for renal toxicity; however, it could also be associated with changes in therapy. When adverse events were severe due to underlying disease, dose reduction, or cycle delay did not adequately impact therapy completion, and required further therapy monitoring. Long-term occurrence of myelodysplasia syndrome was 1.8%, comparable to reported occurrences requiring further monitoring. Our analysis reinforces that ¹⁷⁷Lu-DOTATATE is an effective, well-tolerated treatment for NETs with low incidences of long-term adverse events.

Neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs) are rare, hormone producing neoplasms that are derived from neuroendocrine hormone producing cells often found in the intestines, pancreas, and lungs.¹ Although gastroenteropancreatic neuroendocrine (GEP-NETs) can be managed by surgical resection in early stages of disease, in advanced stages with metastatic disease, resistance to conventional treatments, such as external beam radiation and chemotherapy, is rampant, leading to deteriorating quality of life.² The high hormonal burden seen in NETs corresponded to a 5-year survival of <50% in metastatic disease requiring symptomatic management.³ Long-acting somatostatin analogs have been used to control symptoms and stabilize patients, but when there is disease progression, treatment is required.⁴

¹⁷⁷Lutetium-DOTATATE (Lutathera, Novartis) was approved by the United States Food and Drug Administration in 2018 to be a systemic treatment for patients with GEP-NETs.^{5 177}Lu-DOTATATE binds to overexpressed somatostatin receptor type 2 (SSTR2) on the tumor surface which is then internalized allowing the decaying ¹⁷⁷Lu to deliver radiation dose through beta decay, leading to single and double stranded DNA breaks, which ultimately trigger tumor cell death. ¹⁷⁷Lu-DOTATATE is well tolerated, with major side effects during treatment most likely attributed to the amino acid infusion required for renal protection. Antiemetic prophylaxis can be given to reduce the occurrence of these side effects.⁶ Acute side effects normally occur within 24 hours of radiopharmaceutical infusion and present as nausea/vomiting and abdominal discomfort. Rare incidences (>1%) of hormonal crises (carcinoid crisis) are triggered by tumoricidal effects due to treatment (increased hormone release due to cell death), but have been managed accordingly.^7,8

Safety data on ¹⁷⁷Lu-DOTATATE were obtained in the phase I/II clinical trial conducted at Erasmus Medical Center (Rotterdam, the Netherlands) in 2000, with a heterogenous group of 615 patients with GEP-NETs, melanoma, thyroid, non–small cell lung cancer (NSCLC) and other cancers. Patients were treated with 7.4 GBq (200 mCi) doses every 8 weeks for 4 cycles, and the patients were monitored for 10 years. Acute side effects due to therapy were nausea (25%), vomiting (10%), and abdominal pain or discomfort (10%). Hematological toxicity occurred in 12.8% of the treated population, with 4.1% leukopenia [using the National Cancer Institute (NCI), common terminology criteria for adverse events v5.0, CTCAE, a grade 3–4], 4.9% anemia (grade 3–4), and 7.2% thrombocytopenia (grade 3–4). Risk factors for grade 3 and 4 toxicity included older age (above 70 y old), prior chemotherapy, creatinine clearance <60 mL/min/1.73 m^2, and presence of bone metastases.⁹

The subsequent NETTER-1 trial that led to approval of ¹⁷⁷Lu-DOTATATE was a phase III clinical trial conducted across 41 centers in 8 countries from 2012 to 2016. At least 79% of NETTER-1 patients completed all 4 cycles of therapy, and it was found that at least 2 cycles of therapy were required for successful outcomes [defined as progression-free survival, with secondary objectives of 20% objective response rate, overall survival (n.s.), improved quality of life metrics, and tolerable safety and side effect profiles]. In the NETTER-1 trial, commonly reported adverse events were nausea (59%) and vomiting (47%), attributed mainly to the amino acid infusion that was total parental nutrition (TPN).^3,6 Transient hematological events were observed, including grade 3–4 lymphopenia (9%), thrombocytopenia (2%), and neutropenia (1%).³

Due to observed hematological adverse events, in practice, posology strategies including dose reduction [by 50% leading to a 3.7 GBq (100 mCi) infusion], or cycle delay (16 wk between cycles) have been used to improve therapy tolerance and patient outcomes. The objective of this study was to determine the efficacy of posology strategies and their impact on short-term and long-term adverse events in patients who received ¹⁷⁷Lu-DOTATATE at the University of Michigan (UM).

PATIENTS AND METHODS

Patient Characteristics, Inclusion, and Exclusion Criteria

We conducted a retrospective, single-center observational study with 173 patients treated with ¹⁷⁷Lu-DOTATATE at the University of Michigan between June 2019 and November 2021. Institutional Review Board (IRB) permission was obtained for this retrospective analysis (HUM00197422, approved March 31, 2021). Records were searched for patients referred to UM for ¹⁷⁷Lu-DOTATATE therapy. The eligibility criteria were met if patients presented with metastatic or locally advanced, inoperable, midgut carcinoid NETs and metastatic GEP-NETs (foregut and hindgut, pancreatic NETs) with progressive disease under somatostatin analog therapy. In addition, the presence of metastasized or locally advanced NET, inoperable (for curative intent), regardless of the origin of the tumor, and a Ki₆₇ index ≤20% (grade 1 and grade 2), with a small number of grade 3 with Ki₆₇ index >20% included. Patients also received a pretreatment ⁶⁸Ga-DOTATATE PET/CT (or ⁶⁴Cu-DOTATATE PET/CT) scan to confirm target lesions overexpressing somatostatin. Patients with a Krenning score of 3–4 were enrolled in therapy.^10,11 Patients were contraindicated to ¹⁷⁷Lu-DOTATATE therapy if any of the following were met: (1) blood values outside the threshold limit described in the NETTER-1 trial,³ (2) female patients of childbearing potential, (3) on therapies within <4 weeks before planned treatment, or on short-acting or long-acting octreotide where treatment cannot be interrupted, or (4) co-existing malignancies or untreated, nonstabilized brain metastasis.

Laboratory Testing Protocols, Parameters, and Patient Preparation

Within 2 weeks before each ¹⁷⁷Lu-DOTATATE treatment cycle, the patient’s laboratory values (WCC, white cell count; LYM, lymphocyte count; ANC, absolute neutrophil count; Hb, hemoglobin; PLT, platelets; eGFR, estimated glomerular filtration rate; SrCr, serum creatinine; bilirubin; Alb, albumin; ALP, alkaline phosphatase; CgA, chromogranin A) were obtained and assessed to ensure values were above the thresholds for treatment (Table 1). Patient laboratory values were compared with current guidelines, drug package inserts, and institutional experience to determine “ideal therapy candidate,” “borderline therapy candidate,” or “not therapy candidate.”⁵ When indicated, a pregnancy test was performed 3 days before therapy. Long-acting somatostatin analog therapy was discontinued around 4 weeks before therapy and continued within 24 hours after treatment. Within 24 hours of ¹⁷⁷Lu-DOTATATE therapy, short-acting somatostatin analogs were discontinued. Six weeks after therapy, patients followed up with their referring oncologist (or endocrinology team) to reassess side effects, laboratory values, risk and benefit, and inclusion for the subsequent ¹⁷⁷Lu-DOTATATE cycle.

TABLE 1.

Laboratory Value Thresholds for Therapy Enrollment

Parameters	Ideal Therapy Candidate	Borderline Therapy Candidate		Not Therapy Candidate
	Initial & Follow Up	Initial	Follow Up*	Initial	Follow Up
Albumin (g/dL)	>3	2–3	—	<2	<2 or <3 & ↑ PTT
Prothrombin time (PTT)	WNL	Borderline	—	Elevated
Absolute neutrophil count (109 cell/L)	≥1.5	1.0–1.5	Delay until grade 2†	<1
Bilirubin (mg/dL)	<3.5 (<3xULN)	3 (~3×ULN)	Delay until at baseline‡	>3.5 (>3×ULN)
eGFR (mL/min/1.73 m2)	>50	30–49	Delay until at baseline§	<30 (or HD)
Hemoglobin (g/dL)	>8	~8	Delay to grade 2 (or transfusion >8 g/dL)║	<8
Platelet count (109 cell/L)	≥75	50–75	Delay to grade 1¶	<50
White blood cell count (109 cell/L)	≥2	~2	—	<2	NA

^*Any of these parameters will require a 50% dose reduction. If the borderline parameters do not improve after a 16-week delay, the therapy should be discontinued.

^†Defined as grade 3 ANC 0.5–1 and grade 4 ANC <0.5.

^‡Defined as bilirubin rising to near 3.5 mg/mL (>3×ULN grade 3 or 4 toxicity) or Alb (<3 with elevated prothrombin, prothrombin ratio <70%).

^§Defined as >40% increase in baseline Cr but eGFR >30.

^║Defined as grade 3 HgB <8 or new transfusion requirement or grade 4 life-threatening anemia requiring intervention.

^¶Defined as grade 2 PLT 50–75 or grade 3 PLT 25–50 or grade 4 PLT <25.

↑ indicates increased; ULN, upper limit of normal; WNL, within normal limits.

Posology: Dose Reduction and Cycle Delay Protocol

After enrollment into therapy, either 7.4 GBq (200 mCi±10%, full dose) or 3.7 GBq (100 mCi±10%, reduced dose) of ¹⁷⁷Lu-DOTATATE was infused intravenously. As suggested by the ¹⁷⁷Lu-DOTATATE package insert, patients would then receive an 8±1-week recommended recovery period with cycle delay (>16 wk between therapy doses) when tolerability was an issue or if monitoring parameters are borderline.⁵ Posology for ¹⁷⁷Lu-DOTATATE was completed if patients had severe adverse reactions or met the dose-modifying toxicity criteria (Table 1). For patients with thrombocytopenia of grade 2 or higher, treatment would be suspended and laboratory blood values would be monitored every 2 weeks (and treated as required, for renal failure with appropriate hydration when permissible). If the observed toxicity continued beyond 16 weeks, therapy was discontinued. If the observed toxicity resolved within 16 weeks, dose reduction was used. If dose reduction was tolerated, subsequent treatment could be rechallenged using the full dose (7.4 GBq, 200 mCi), but if patients continued to experience adverse reactions, therapy was discontinued. With this protocol, 6 patients received both dose reduction and cycle delay. For renal protection, a compounded amino acid containing 25 g L-lysine and 25 g L-arginine was infused 30 minutes before ¹⁷⁷Lu-DOTATATE administration over 4 hours. When required, antiemetic prophylaxis (ondansetron, diphenhydramine, prochlorperazine, and/or metoclopramide) was also given 30 minutes before infusion. Patients received up to 4 cycles of therapy if tolerated and monitoring parameters remained within limits.

Statistical Analysis

Pertinent information from the clinical medical charts was reviewed to obtain patient demographics, ¹⁷⁷Lu-DOTATATE dosing, laboratory values, clinical care notes, and adverse events (related to therapy, disease progression, or unrelated). Data were collected for each patient, including laboratory parameters recorded at baseline (within 6 wk before therapy), after cycles 1–4 for each treatment (2 wk after the day of therapy), after the last therapy dose, and 3, 6, 9, 12, 18, 24, 36 months after therapy. Renal toxicity was defined as an estimated creatinine clearance <40 mL/min/1.73 m², or a 40% increase in serum creatinine (Cr) compared with the baseline, and a >40% decrease in creatinine clearance compared with baseline. Liver toxicity was defined as either: (1) bilirubinemia >3 times the upper limit of normal (ULN), or (2) hypoalbuminemia <30 g/L with a decreased prothrombin ratio to <70%. The remaining laboratory blood values were compared with the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0), with grade 3 or 4 adverse events explicitly stated.¹² The ¹⁷⁷Lu-DOTATATE dosing information, laboratory values, and adverse events data were analyzed using GraphPad Prism 10.2.2 (univariate analysis using the Fischer exact test, and Wilcoxon matched pair signed rank test). In addition, a linear mixed-effects model was applied for each biomarker to assess the relationship between biomarker values and sampling time, while accounting for interindividual variability. The model included both a random intercept and a random slope for sampling time at the patient level, denoted as: biomarker value ~ sampling time + (1 +sampling time|patient). In this model, the fixed-effect slope represents the overall temporal trend of the biomarker across the population. To further evaluate whether the rate of change differed across time intervals, sampling time was stratified into 2 periods: short-term (<3 mo after final cycle of therapy) and long-term (from 3 mo after final cycle of therapy to final follow-up). Separate mixed-effects models were then used to assess whether biomarker changes within each period were statistically significant.

RESULTS

Patient Characteristics

The patient characteristics are listed in Table 2. A total of 173 patients were enrolled in ¹⁷⁷Lu-DOTATATE therapy between June 2019 and November 2021. In all, 100 patients were male (57.8%), and 73 patients were female (42.2%) with a mean age of 64±10.6 years old (range 34–90 y old). For patients who received all 4 cycles of ¹⁷Lu-DOTATATE (n=141), the average time to completion of therapy was 175±26 days, and the average number of cycles was 3.6 for all patients (n=173). Most patients had NETs of grade 2 (41.0%), followed by grade 1 (26.0%) and grade 3 (6.4%). For 46 patients (26.6%), a NET grade was not determined. Using a ⁶⁸Ga-DOTATATE PET scan, the median Krenning score was 4.

TABLE 2.

Patient Characteristics

Characteristics	N (%)	Therapy Completion	Discontinued Therapy	% Completed	Univariate Analysis*
All patients	173	141	32	81.5
Sex
Male	100 (57.8)	82	18	82.0	0.846
Female	73 (42.2)	59	14	80.8
Age
≤40	6 (3.5)	5	1	83.3	0.403
Between 40 and 60	44 (25.4)	33	11	75.0
≥60	123 (71.1)	103	20	83.7
Grading
Grade 1 (Ki67 <2%)	45 (26.0)	39	6	86.6	0.022
Grade 2 (Ki67 3%–20%)	71 (41.0)	59	12	83.1
Grade 3 (Ki67 >20%)	11 (6.4)	6	5	54.5
Unknown	46 (26.6)	36	10	78.3	Not included
Primary tumor location
Midgut or foregut	81 (46.8)	72	9	88.9	0.007
Pancreatic	40 (23.1)	27	13	67.5
Bronchial	12 (6.9)	10	2	83.3
Chromaffin tissues	5 (2.9)	5	0	100
Head & neck	2 (1.2)	2	0	100
Spinal cord	1 (0.6)	0	1	0
Thymus	1 (0.6)	0	1	0
Unknown	31 (17.9)	25	6	80.6	Not included
Neuroendocrine subtype
Carcinoma	158 (91.3)	128	30	81.0	0.247
Pheochromocytoma	4 (2.3)	4	0	100
Gastrinoma	1 (0.6)	0	1	0
Glucagonomas	1 (0.6)	1	0	100
Neuroblastoma	1 (0.6)	0	1	0
Paragangliomas	1 (0.6)	1	0	100
More than 1 subtype (MEN-1)	3 (1.7)	3	0	100
Not indicated in the medical chart	4 (2.3)	4	0	100	Not included

^*Univariate analysis was performed by the Fisher exact test with statistical significance set at P < 0.05. The univariate analysis was used to determine if there was a difference in therapy completion or discontinuation between the subgroups of sex, age, grading, primary tumor location, and neuroendocrine subtype.

Significant P<0.05 values are in bold

MEN-1 indicates multiple endocrine neoplasia type 1.

Primary tumor location was predominantly in the midgut and foregut (46.8%) and pancreas (23.1%). However, there was also some NET localization in the lungs (6.9%), chromaffin tissues (2.9%), head and neck (1.2%), spinal cord (0.6%), and thymus (0.6%). Most patients presented with neuroendocrine carcinomas (91.3%); however, there were 4 patients with pheochromocytoma (2.3%) and 3 patients with multiple endocrine neoplasia type 1 (1.7%).

Treatment Dose Reduction, Cycle Delay, and Ancillary Medications on Therapy Completion

Of the 173 patients who were enrolled in ¹⁷⁷Lu-DOTATATE therapy, 141 patients (81.5%) completed all 4 cycles. In all, 16 patients (9.2%) discontinued therapy after the first cycle, 7 patients (4.0%) after the second cycle, and 9 patients (5.2%) after the third cycle. Of the 32 patients where dose discontinuation was necessary, the most common reason was due to disease progression requiring hospice (12 patients, 37.5%), followed by: disease progression requiring a change in therapy (10 patients, 31.3%), pancytopenia (5 patients, 15.6%), renal failure (2 patients, 6.3%), liver failure (1 patient, 3.1%), renal obstruction (1 patient, 3.1%), and seizures during treatment (1 patient, 3.1%). There was also a significant relationship between neuroendocrine tumor grade (P=0.022) and primary tumor location (P=0.007) on therapy completion rate (Table 2).

Dose reduction was suggested for 13 patients (7.5%). The most common reason for dose reduction was acute or chronic renal impairment (7 patients, 53.8%), followed by pancytopenia (3 patients, 23.1%), thrombocytopenia (2 patients, 15.4%), and an overall heavy bone burden (1 patient, 7.7%). Of the 13 patients who received a dose reduction, 9 patients (69.2% success rate) were still able to complete all 4 cycles of therapy (Table 2).

Cycle delay occurred in 36 patients (20.8%). The most common reasons for cycle delay were due to adverse events from treatment (11 patients, 30.1%) and comorbidities that led to a decline in function (11 patients, 30.1%). The remaining delays were due to medical shortages and insurance delays (3 patients, 8.3%), or other minor delays (defined as delays <4 weeks after the 8-week recovery period between cycles, 8 patients, 22.2%). Of the 36 patients who experienced delays, 20 patients (55.5% success rate) were still able to complete all 4 cycles of therapy. In the subset of the 20 patients that completed therapy with delays, 5 patients had delays due to unplanned reasons, which had a therapy completion rate of 23.8% (Table 3).

TABLE 3.

Dose Reduction, Cycle Delay, and Therapy Completion

Posology	N	No	Yes	Univariate Analysis*
Dose reduction, n (%)
Cycle 1	173	165 (95.4)	8 (4.6)	0.390
Cycle 2	157	152 (96.8)	5 (3.2)
Cycle 3	150	150 (98.7)	2 (1.3)
Cycle 4	141	137 (97.2)	4 (2.8)
Sum	621	602 (96.9)	19 (3.1)
Cycle delay, n (%)
Cycle 1	173	173 (100)	0	Not included
Cycle 2	157	145 (92.4)	12 (7.6)	0.554
Cycle 3	150	135 (90.0)	15 (10.0)
Cycle 4	141	125 (88.7)	16 (11.3)
Sum	621	578 (93.1)	43 (6.9)

^*Univariate analysis was performed by the Fisher exact test with statistical significance set at P<0.05. The univariate analysis was used to determine if there was a significant difference in posology use between cycles of therapy.

Patients who received ¹⁷⁷Lu-DOTATATE also received an amino acid infusion for renal protection. Depending on the patient’s symptoms before receiving therapy, the patient was given antiemetic prophylaxis (Supplemental Fig. S1, Supplemental Digital Content 1, http://links.lww.com/CNM/A581). During the initial cycle of therapy, 135 patients (78.0%) received one antiemetic with diphenhydramine. Throughout the 621 administered doses, only 1 administration required 2 antiemetics and a rescue antiemetic during amino acid infusion. Besides this, 21 administrations (3.4%) required 2 antiemetics, and 20 administrations (3.2%) only required amino acid infusion with or without diphenhydramine. After 4 cycles of therapy, 68.7% of patients de-escalated antiemetic prophylaxis and no longer required diphenhydramine. Only 3.5% of the patients required prophylaxis escalation.

Blood Values and Adverse Events during Treatment

During 4 cycles of therapy, patients reported various gastrointestinal, vascular, cutaneous, nervous system, and respiratory adverse effects (Supplemental Table S1, Supplemental Digital Content 1, http://links.lww.com/CNM/A581). Overall, half of the patients reported adverse effects both during and 1–2 days following ¹⁷⁷Lu-DOTATATE infusion, whereas the other half of the patients reported no adverse effects. The most common reported side effect was nausea (15.6% of all administered doses), followed by fatigue (9.5%). Most of the remaining adverse effects occurred in <5% of all administered doses. Of the 173 patients who received therapy, there were 6 cases of severe adverse events (3.5%) requiring admission to the emergency department. These severe adverse event were as follows: (1) patient developed severe hypoglycemia requiring subsequent blood glucose monitoring, (2) patient developed carcinoid crisis and bradycardia syndrome which was managed by switching the amino acid infusion to a normal saline infusion and subsequent monitoring in the emergency room, (3) patient developed shortness of breath with hypotension related to carcinoid crisis which the patient received 250 μg octreotide bolus and an infusion of octreotide at 50 μg/h until the blood pressure was stabilized, (4) patient had seizures during treatment following pulseless electrical activity requiring resuscitation in the emergency department, (5) patient developed hepatorenal syndrome after treatment requiring admission to the ICU, and (6) patient had persistent neurological symptoms which made treatment complicated as the tumor metastasized to the dural mater of the brain requiring therapy discontinuation.

Comparing the blood, renal, and liver function values to the CTCAE parameters indicated short-term adverse events (Table 4). At baseline, most patients had grade 0 or grade 1 parameters, with 1 patient (0.7%) having grade 4 neutropenia, 6 patients (4.8%) with grade 3 lymphocytopenia, 2 patients (1.2%) with grade 3 hypoalbuminemia, and 1 patient with grade 3 declined eGFR. After each treatment, severe (grade 4) leukopenia was experienced in 2 (0.4%) administrations, and lymphocytopenia in 1 (0.2%) administration. When comparing CTCAE scores (for grades 3 and 4 vs. grades 0 through 2) between patients who completed therapy and those who discontinued therapy, only alkaline phosphatase (P=0.002), chromogranin A (P=0.009), eGFR (P=0.037), and lymphocyte count (P=0.026) was significantly different between the groups (Supplemental Table S2, Supplemental Digital Content 1, http://links.lww.com/CNM/A581).

TABLE 4.

Baseline and Cycle 4 Adverse Events According to CTCAE Criteria

	Labs	Grade 0 or Grade 1	Grade 2	Grade 3	Grade 4	No Data
Baseline
Hypoalbuminemia	↓Alb	161 (96.4%)	4 (2.4%)	2 (1.2%)		6
Elevated alkaline phosphatase*	↑ALP	101 (60.1%)	—	—	—	5
Neutropenia	↓ANC	139 (99.3%)	0	0	1 (0.7%)	33
Hyperbilirubinemia†	↑Bili	148 (93.1%)	—	—	—	14
Elevated creatinine	↑Cr	163 (99.4%)	1 (0.6%)	0	0	9
Elevated chromogranin A‡	↑CgA	28 (27.7%)				72
Declined renal filtration	↓eGFR	147 (86.0%)	23 (13.5%)	1 (0.6%)	0	2
Anemia	↓HgB	157 (92.4%)	13 (7.7%)	0		3
Lymphocytopenia	↓LYM	105 (84.7%)	13 (10.5%)	6 (4.8%)	0	49
Thrombocytopenia	↓PLT	168 (100%)	0	0	0	32
Leukopenia	↓WCC	167 (98.2%)	3 (1.8%)	0	0	3
Following treatment cycles after baseline
Hypoalbuminemia	↓Alb	452 (95.4%)	14 (3.0%)	8 (1.7%)		80
Elevated alkaline phosphatase	↑ALP	461 (98.5%)	4 (0.9%)	3 (0.6%)	0	85
Neutropenia	↓ANC	443 (98.2%)	8 (1.8%)	0	0	113
Hyperbilirubinemia	↑Bili	461 (97.9%)	9 (1.9%)	1 (0.2%)	0	83
Elevated creatinine	↑Cr	469 (98.7%)	6 (1.3%)	0	0	76
Elevated chromogranin A‡	↑CgA	68 (25.6%)				408
Declined renal filtration	↓eGFR	377 (80.2%)	92 (19.6%)	1 (0.2%)	0	83
Anemia	↓HgB	425 (89.3%)	45 (9.5%)	6 (1.3%)		75
Lymphocytopenia	↓LYM	273 (64.2%)	107 (25.2%)	44 (10.4%)	1 (0.2%)	139
Thrombocytopenia	↓PLT	468 (98.5%)	6 (1.3%)	1 (0.2%)	0	76
Leukopenia	↓WCC	462 (96.7%)	13 (2.7%)	1 (0.2%)	2 (0.4%)	73

Note: The criteria for grade 4 hypoalbuminemia and anemia are not a numeric parameter and therefore are omitted.

^*Baseline alkaline phosphatase was used to assess if patient values were within normal limits (WNL) or elevated at baseline to determine treatment CTCAE grades [at baseline, 101 patients (60.1%) were WNL, 67 patients (40.0%) were elevated].

^†Baseline bilirubin (Bili) was used to assess if patient values were WNL or elevated at baseline to determine treatment CTCAE grades [at baseline, 148 patients (93.1%) were WNL, 11 patients (6.9%) were elevated].

^‡Chromogranin A values were determined to be WNL or elevated. At baseline, 73 patients (72.3%) had elevated chromogranin A. During treatment, 198 administrations (74.4%) led to elevated chromogranin A.

Long-term Adverse Events

Following ¹⁷⁷Lu-DOTATATE therapy, the patient’s blood values were analyzed up to 3 years (Fig. 1). Based on fixed effects from the mixed-effects model (Supplemental Table S3, Supplemental Digital Content 1, http://links.lww.com/CNM/A581), eGFR showed a statistically significant decline over the follow-up time (slope =−0.174 mL/min/1.73 m² per month, P<0.01). In the short-term period (<3 mo after treatment) no significant trend was observed (slope = 0.02 mL/min/1.73 m² per month, P=0.873) whereas the decline was statistically significant in the long-term period (slope =−0.16 mL/min/1.73 m² per month, P<0.05). Treatment-related decline of 8.35 mL/min/1.73 m² over 4 years observed in this study, exceeds the age-related decline reported in the literature, 4.08 mL/min/1.73 m² over 4 years, for individuals around 60 years old.^13,14 A similar long-term decline was also observed for albumin, alkaline phosphatase, and bilirubin, while short-term changes were not statistically significant. In contrast, hemoglobin and lymphocytes significantly declined across all timeframes (short-term, long-term, and overall). For absolute neutrophil count and platelets, a significant decline was observed in the short term, followed by signs of recovery in the long-term period.

FIGURE 1.

Blood lab values were collected at baseline, after cycles 1–4 of ¹⁷⁷Lu-DOTATATE treatment, and during follow-up out to 3 years. Measured blood values for patients at baseline, after cycles 1–4 of ¹⁷⁷Lu-DOTATATE therapy, and during following up out to 3 years. The purple line represents the CTCAE criteria cut-off used for within normal range (grade 0) and/or elevated or decreased lab values (grade 1–4). For eGFR, the CTCAE cutoff for grade 1 and grade 2 was used. Sample size (n) is included in parentheses after each time point.

In patients who received ¹⁷⁷Lu-DOTATATE, only one patient developed myelodysplasia syndrome, which was identified 3 months after the final cycle therapy. A second patient had blood values indicating myelodysplasia syndrome after 3.5 years, but the diagnosis was not confirmed since the patient did not want to receive a bone biopsy to confirm. There was a 1.83% incidence of myelodysplasia syndrome (2/109).¹²

Patients Receiving Blood Transfusions

Of the 173 patients who received 4 cycles of Lutathera, one patient had a hemoglobin (Hgb) level <8 consistently (Hgb = 7.86±1.12 g/dL). The patient received 4 red blood cell (RBC) transfusions throughout their Lutathera treatment—2 RBC units ∼2 months before first Lutathera treatment, 2 RBC units ∼1 week before first Lutathera treatment, 2 RBC units ∼1 day before second Lutathera treatment, 2 RBC units ∼1 week before fourth Lutathera treatment—and was able to complete all 4 cycles without delay and/or dose reduction. No platelet transfusions nor colony-stimulating factors for white cells/neutrophils were used.

DISCUSSION

Of the patients who were enrolled in ¹⁷⁷Lu-DOTATATE therapy, tumor grading and primary tumor location impacted therapy completion, which is to be expected, as higher-grade NET is associated with worsened prognosis and complications leading to therapy discontinuation.^15,16 In addition, therapy discontinuation was also considered for quality of life and hospice considerations. Differences in primary tumor location on therapy completion are related to NET aggressiveness, and the significant findings are attributed to smaller sample sizes due to limited patients presenting with head and neck, spinal cord, or thymus NETs.

The use of posology was not significantly different between treatment cycles. Instead, dose reduction with or without cycle delay help increase therapy tolerance and is used in concert with blood values to determine therapy continuation. Unlike dose reduction, which was always documented in clinical charts and rationalized, cycle delay was not always justified due to medical delays or other non–therapy-related issues, which made analysis difficult. Unplanned delays had a significant decrease in success rate when compared with known reasons for delay, which can be attributed to disease progression requiring other hospitalizations, or interventions which may not have been recorded. The use of dose reduction led to a higher therapy completion compared with cycle delay, which favors dose reduction when blood values are borderline for the next cycle of treatment. Renal function was also used to determine therapy enrollment, as low pretherapy eGFR or high pretherapeutic kidney uptake has shown to be the sole variable in predicting ¹⁷⁷Lu-DOTATATE nephrotoxicity.¹⁷ Nonetheless, blood values and renal function were used to determine posology changes, which helped improve overall therapy completion rate. The therapy completion rate with indicated posology strategies (81.5%) is comparable to the NETTER-1 trial (77%), showing successful therapy intervention in a diverse patient population with unique NET presentations and subtypes.

Antiemetic prophylaxis before amino acid and ¹⁷⁷Lu-DOTATATE infusion is required due to known short-term reactions associated with amino acid infusion.³ Patients were started on ondansetron with or without diphenhydramine, where only 3.4% of patients required an escalation in prophylaxis. Most patients did not require diphenhydramine, with limited reported reactions due to amino acid administration. The occurrence of side effects due to amino acid and therapy infusion was significantly less than the reported short-term reactions in the NETTER-1 trial (nausea, 59% vs. 16%, vomiting 47% vs. 4.7%) demonstrating the benefits for using antiemetic prophylaxis and a 2 amino acid blend. Overall reported side effects were less than that of NETTER-1 (50% vs. 86%), reinforcing the implementation of therapy prophylaxis. Prophylaxis also helped with symptom management by withholding somatostatin therapy before ¹⁷⁷Lu-DOTATATE.

Carcinoid crisis occurred in 2 (1.2%) patients, with an onset of 3 hours in one patient and the day after in the second patient. The rate of carcinoid crisis onset was greater than the NETTER-1 trial (<1%), which was attributed to patients presenting with higher-grade NET than patients in the NETTER-1 trial. Patients who developed carcinoid crisis were managed and given octreotide injections. Although this would help with symptom control, the efficacy of ¹⁷⁷Lu-DOTATATE could be diminished with octreotide injection therefore supportive care is often the first line of action.¹⁸ Overall, severe adverse events were related to underline disease which was exacerbated from ¹⁷⁷Lu-DOTATATE therapy. Patients who developed severe adverse events, within 30 minutes to 1 hour after therapy initiation were admitted to the emergency department and managed subsequently resolving the issues.¹⁹ This contributed to therapy discontinuation as patients were not rechallenged.

The difference between short-term blood values at baseline and at cycle 4 was statistically significant, and the occurrence of Grade 3 and 4 neutropenia (0% vs. 1%), thrombocytopenia (0.2% vs. 2%), and lymphocytopenia (10.6% vs. 9%) was comparable to the NETTER-1 trial. The difference in alkaline phosphatase and glomerular filtration rate between baseline and cycle 4 was also statistically significant; however, grades 3 and 4 were <1%. Therefore, a decline in function was present but generally not severe. Significant changes in alkaline phosphatase and bone marrow function were consistent with reported laboratory values following treatment.²⁰ Differences in alkaline phosphatase and glomerular filtration rate between patients who completed therapy and discontinued therapy between CTCAE grade 3 or 4 and grade <2 were significant indicating that hepatic and renal function was important in therapy completion. Alkaline phosphatase is a known adverse prognostic indicator in NET/NEN. Patients presented with elevated white blood cell count and neutrophil count were checked for possible sources of infection. These patients were not infected and had elevated white blood cell count and neutrophil count due to other co-morbidities. One patient had a hemoglobin level consistently <8 and received 4 transfusions throughout their Lutathera treatment. Transfusions enabled the patient to complete all 4 cycles of Lutathera without delay and/or dose reduction.

Long-term blood value trends from 3 months after therapy out to 36 months indicated that the initial decline in absolute neutrophil counts and platelets was transient, which rebounded after 3 months. Hemoglobin was significantly decreased at all time frames. However the occurrence rate of myelodysplasia syndrome was similar to literature reported values (1.83% vs. 2.35%), indicating long term adverse events are rare (<2%) which requires further monitoring.²¹ Since treatment-altering hematological toxicity is limited, it can be difficult to predict even from posttherapeutic bone marrow uptake.²² Glomerular filtration rate in the short term was not significant; however, in the long term demonstrated a 8.35 mL/min/1.73 m² decline over the 4-year follow up period.²⁰ This exceeds the expected age-associated decline of 4.08 mL/min/1.73 m² over the same 4-year period, suggesting a potential risk for long-term toxicity.¹⁴ Contrary to the observed results from the retrospective analysis by Baum et al²³ in 1281 patients with neuroendocrine neoplasms (total of 4709 treatment cycles), which did not indicate a statistically significant decline in renal function or signs of long-term nephrotoxicity, further studies are required to determine the risk for nephrotoxicity. In addition, long-term changes in renal function can also be attributed to other factors such as changes in treatment (chemotherapy or radiation therapy), or other co-morbid diseases which would need to be explored.

CONCLUSIONS

The introduction of a new treatment for NET requires monitoring for adverse events. When adverse events are mild, posology, either dose reduction or cycle delay, led to improved therapy tolerance in patients with borderline laboratory values. However, between dose reduction and cycle delay, dose reduction led to a greater increase in completion of all 4 cycles of therapy. Although the initial completion rate was low, when looking at all 173 patients, the therapy completion rate was similar to the NETTER-1 trial, with similar reported adverse events. Neutropenia and thrombocytopenia were observed; however, these changes in blood values were transient and rebounded long-term. Although renal function continued to decline after treatment, this decrease could be attributed to changes in therapy after ¹⁷⁷Lu-DOTATATE, which can complicate the analysis. When adverse events are severe or present due to underlying disease progression, dose reduction and cycle delay do not adequately address the presentation and do not lead to an increase in therapy completion. Our analysis confirms that PRRT is an effective, well-tolerated treatment with a low incidence of long-term side effects. Potential risks for long-term renal toxicity require further investigation.

Supplementary Material

rlu-50-1144-s001.docx ^{(249.8KB, docx)}