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Initial experience and lessons learned with implementing Lutetium-177-dotatate radiopharmaceutical therapy in a radiation oncology–based program

      Abstract

      Purpose

      To assist radiation oncology centers in implementing Lutetium-177-dotatate (177Lu) radiopharmaceutical therapy for midgut neuroendocrine tumors. Here we describe our workflow and how it was revised based on our initial experience on an expanded access protocol (EAP).

      Methods

      A treatment team/area was identified. An IV-pump-based infusion technique was implemented. Exposure-based techniques were implemented to determine completion of administration, administered activity, and patient releasability. Acute toxicities were assessed at each fraction. A workflow failure modes and effects analysis (FMEA) was performed.

      Results

      A total of 22 patients were treated: 11 patients during EAP (36 administrations) and 11 patients after EAP (44 administrations). Mean 177Lu infusion time was 37 min (range 26–65 min). Mean administered activity was 97% (range 90–99%). Mean patient exposures at 1 m were 1.9 mR/h (range 1.0–4.1 mR/h) post-177Lu and 0.9 mR/h (range 0.4–1.8 mR/h) at discharge, rendering patients releasable with instructions. Treatment area was decontaminated and released same day. All patients in the EAP experienced nausea, and nearly half experienced emesis despite premedication with antiemetics. Peripheral IV-line complications occurred in six treatments (16.7%), halting administration in 2 cases (5.6%). We transitioned to peripherally inserted central catheter (PICC)-lines and revised amino acid formulary after the EAP. The second cohort of 11 patients after EAP were analyzed for PICC-line complications and acute toxicity. Nausea and emesis rates decreased (nausea G1+ 61%–27%; emesis G1+ 23%–7%), and no PICC complications were observed. FMEA revealed that a failure in amino acid preparation was the highest risk.

      Conclusion

      177Lu-dotatate can be administered safely in an outpatient radiation oncology department.

      Keywords

      Introduction

      Lutathera (Advanced Accelerator Applications, Saint-Genis-Pouilly, France), or 177Lu-dotatate (177Lu-DOTA-0-Tyr3-Octreotate), is a peptide receptor radionuclide therapy (PRRT) used to treat either metastatic or inoperable somatostatin receptor–positive gastroenteropancreatic-neuroendocrine tumors (NETs) (
      • Strosberg J.
      • El-Haddad G.
      • Wolin E.
      • et al.
      Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors.
      ,
      • Martini C.
      • Buxbaum S.
      • Rodrgues M.
      • et al.
      Quality of life in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy: information from a monitoring program in clinical routine.
      ). The amino acid peptide, dotatate, is bound to the radionuclide, lutetium-177 (177Lu, T1/2 = 6.65 days), which is primarily a β-emitter (0.498 MeV max, 0.133 MeV mean) (
      ). An international, multi-institutional Phase 3 randomized trial reported improved progression-free survival when Lutathera was added to octreotide (
      • Strosberg J.
      • El-Haddad G.
      • Wolin E.
      • et al.
      Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors.
      ), suggesting Lutathera is a promising treatment option for patients with advanced midgut NET.
      Although Lutathera had been in use in Europe for several years, it was only available in the United States through an expanded access protocol (EAP) until recent FDA approval in January 2018. At the time of approval, published literature on how to administer Lutathera in the clinic was limited. Concomitant infusion of amino acids for 4 h for renal protection, primary elimination via urinary excretion (
      • Calais P.J.
      • Turner J.H.
      Radiation safety of outpatient 177Lu-octreotate radiopeptide therapy of neuroendocrine tumors.
      ,
      • Bodei L.
      • Buxbaum S.
      • Rodrgues M.
      • Bodei L.
      • Mueller-Brand J.
      • Baum R.P.
      • et al.
      The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours.
      ), and high emesis rates associated with Clinisol 15% (commercial amino acids) (
      • Strosberg J.
      • El-Haddad G.
      • Wolin E.
      • et al.
      Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors.
      ,
      ,
      • Calais P.J.
      • Turner J.H.
      Radiation safety of outpatient 177Lu-octreotate radiopeptide therapy of neuroendocrine tumors.
      ,
      • Hope T.A.
      • Abbott A.
      • Colucci K.
      • et al.
      NANETS/SNMMI procedure standard for somatostatin receptor-based peptide receptor radionuclide therapy with (177)Lu-dotatate.
      ) mandate carefully derived workflows including contamination control, radiation safety, dedicated treatment rooms, and patient-specific bathrooms. Finally, release criteria for patients receiving 177Lu therapies are not provided in the tables of NUREG 1556 Vol. 9 Rev. 2 Appendix U by the NRC (
      • Howe D.B.
      • Beardsley M.
      • Bakhsh S.
      NUREG-1556 Consolidated Guidance about Materials Licenses: Program-specific Guidance about Medical Use Licenses, O.o.F.a.S.M.a.E.M. Programs.
      ). Though the content of this article would typically fall under Nuclear Medicine, we have been seeing a growing interest from our radiation oncology colleagues at other institutions to perform Lu-177 PRRT. Radiation oncologists are the authorized users for unsealed radiopharmaceutical therapies at many hospital systems, including ours. With the publication of the NETTER-1 study (
      • Strosberg J.
      • El-Haddad G.
      • Wolin E.
      • et al.
      Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors.
      ) and limited treatment options for somatostatin analog-refractory NETs, Lutathera is becoming an increasingly sought after treatment. As such, radiation oncologists will be approached by patients and referring providers as the gatekeepers to bringing and delivering Lutathera therapy in hospital systems. We feel that our perspective can provide guidance on how to adapt this procedure to a radiation oncology environment.
      Since FDA approval in early 2018 as the first radioactive drug to treat these rare cancers, radiation oncology centers in the United States are in a position to offer Lu-177-dotatate radiopharmaceutical therapy as a therapeutic option for these patients. The goal of this article is to document (1) our methods for implementing this new radiopharmaceutical therapy in our radiation oncology center, (2) our initial 1-year experience, including possible scenarios that presented with unique challenges, and (3) lessons-learned from this experience and from moving forward with improvements to the process after EAP. To evaluate the robustness of our workflow after EAP, we also performed a failure modes and effects analysis (FMEA) of our process based on AAPM Task Group 100 Report (
      • Huq M.S.
      • Fraass B.A.
      • Dunscombe P.B.
      • et al.
      The report of Task Group 100 of the AAPM: application of risk analysis methods to radiation therapy quality management.
      ).

      Methods

      Clinical environment

      We established a multidisciplinary team in our radiation oncology center that consists of radiation oncologists (authorized users), radiation therapists, radiation safety team, nursing staff, and medical physicists (Fig. 1). The radiation therapist was primarily responsible for the actual physical administration of the Lutathera under the direct supervision of the authorized user (i.e., radiation oncologist). Lutathera was administered in an outpatient setting. Treatment rooms required space for an infusion chair, equipment (blood pressure monitor, infusion pump, etc.), and personnel (1 authorized user, one nurse, one radiation therapist administering activity dosage, and one radiation therapist reading a checklist). Treatment rooms needed to be in areas that could be temporarily shut down with minimal disruption to the clinic if contamination is present (Fig. 2) and near a restroom that could be restricted for sole use by Lutathera patients. Based on several exposure rate measurements in the area from a 186 mCi vial (normalized to a standard 200 mCi dose), lead shielding of the room was not required (see Supplementary Material, Fig. 1).
      Figure thumbnail gr1
      Fig. 1Radiation oncology–based workflow for outpatient Lutathera treatment.
      Figure thumbnail gr2
      Fig. 2Floor plan for administration rooms (yellow), designated restroom (green), transportation route (blue arrow) for Lutathera from the brachytherapy suite (where the vials of activity are received, assayed, and prepared), and stanchions/signage (red lines) restricting traffic.

      Area preparation

      The treatment area is prepared for contamination control by papering floors, restricting access with retractable stanchions, and covering the infusion chair with absorbent material (see Fig. 3). Waste bins are placed throughout the area for radiation waste, including disposal of personal protective equipment (PPE). In the designated restroom, handles are covered with nitrile gloves and the toilet exterior is lined with paper and the seat is covered with plastic. Any other areas that may have patient contact are covered with absorbent paper. Restroom etiquette instructions are also posted.
      Figure thumbnail gr3
      Fig. 3(a) Hallway with stanchions (red) leading to administration rooms (blue) and designated restroom (yellow). Waste bin (green). (b) Designated restroom with gloves on handles (red), paper and plastic lining toilet (yellow), absorbent paper covering railings (green), and posted restroom etiquette instructions (blue). (c) Cart containing Lutathera (green), Nalgene container (red), checklist (blue), survey meter for patient release (orange), and stopwatch (yellow). (d) Lutathera administration, including IV-pump (blue), Lutathera vial in a lead-shielded container and acrylic box (green), and Nalgene container (red). (e-f) Repeat Geiger-Mueller survey readings of the vial.

      Dose/activity assay

      A dose calibrator (CAPINTEC CRC-15BT) was calibrated with 209.2 mCi (25 cc) of 177Lu dotatate in a 30 cc vial, similar to that used for treatment (standard treatment activity is 200 mCi). Channel 10 was used for the measurements, and a calibration factor was established against the vendor's stated activity.
      The dose activity for treatments is assayed by a medical physicist using this dose calibrator and the appropriate setting. The vial of activity is also surveyed using an ionization chamber at a distance of 30 cm to obtain an initial exposure rate (X0) that corresponds to the prescribed activity at the expected time of administration and will be used to determine residual activity after administration, as described in more detail below. Because the pre- and post-administration vial measurements with the ionization chamber survey meter will be used relative to one another, they do not need to be calibrated specific to 177Lu energies, as long as the same device is used.

      Treatment overview

      The treatment regimen in adults consists of four fractions of 200 mCi each (standard), 8 weeks apart, with concomitant infusion of amino acids. Lutathera is supplied as a sterile, colorless, ready-to-use 25 mL solution in a 30 mL clear glass vial. Lutathera must be infused intravenously, ideally using programmable flow rates, via gravity infusion or a programmable infusion pump (bolus injection not permitted) (see Fig. 3) (
      • Hope T.A.
      • Abbott A.
      • Colucci K.
      • et al.
      NANETS/SNMMI procedure standard for somatostatin receptor-based peptide receptor radionuclide therapy with (177)Lu-dotatate.
      ). It is generally recommended that patients are administered antiemetics 30 min before Lutathera administration due to high rates of nausea and emesis (
      ,
      • Hope T.A.
      • Abbott A.
      • Colucci K.
      • et al.
      NANETS/SNMMI procedure standard for somatostatin receptor-based peptide receptor radionuclide therapy with (177)Lu-dotatate.
      ). For renal protection, patients are administered amino acids intravenously for 30–45 min before concomitant intravenous (IV) infusion with Lutathera. There are two lines during Lutathera infusion: (1) a “saline line” and (2) “dose line.” Through the saline line, a 500 mL bag of 0.9% saline is infused via an IV-pump to a short needle inserted into the Lutathera vial. The saline and Lutathera mix and proceed out of the vial through a long needle, also inserted into the vial, connected to the dose line leading to the patient's IV access (
      ,
      • Hope T.A.
      • Abbott A.
      • Colucci K.
      • et al.
      NANETS/SNMMI procedure standard for somatostatin receptor-based peptide receptor radionuclide therapy with (177)Lu-dotatate.
      ). Administration steps are read aloud by one radiation therapist and performed by a second radiation therapist, under authorized user supervision (see Supplementary Materials). A nurse is present to monitor for any infusion problems, that is, blockage or extravasation. Before administration and with a full-dose vial, the administering radiation therapist acquires and records an initial exposure rate measurement from a Geiger-Mueller probe in a specific geometry/orientation. A Geiger-Mueller is more sensitive than an ion chamber survey meter and allows us to discern smaller changes in measurements from the vial amid the large amount of background from the patient and room scatter. This initial measurement will be used as a relative measurement throughout the Lutathera administration to determine a “complete” drug delivery; as such, the device does not need to be calibrated specifically for 177Lu. Lutathera is initially infused at 50 mL/h to evaluate the integrity of flow through the lines. After 5 min, the radiation therapist takes another exposure rate measurement of the vial with the Geiger-Mueller probe, using the same geometry/orientation as the initial exposure rate measurement before the Lutathera infusion began (Fig. 3e). The infusion rate is then increased to 300 mL/h, if the patient is tolerating the procedure well. Measurements with the Geiger-Mueller probe are taken until three consecutive (usually nonzero due to patient IV-line activity) stable exposure rate measurement, 5 min apart, on the Geiger-Mueller probe indicate complete delivery (Fig. 3f). Before halting delivery, we also ensure that the final exposure rate measurement from the Geiger-Mueller probe is less than 10% of the initial measurement. After the entire Lutathera dose has been administered, the IV-line for the dose delivery is disconnected and a red cap is placed on IV-line. The entire delivery system of vial, inserted needles, IV-lines, saline bag, and gloves from the radiation therapist are placed in a Nalgene container and the lid is closed.

      Determination of administered activity

      After administration, the Nalgene container is surveyed at 30 cm (XT) to determine the residual activity using the same ionization chamber survey meter used for assay exposure measurements. The maximum measurement as the Nalgene container is slowly rotated 360° is taken as the post-infusion vial reading (XT) and is corrected for decay to time of administration and for 4% Nalgene attenuation. The percentage of prescribed activity administered to the patient is calculated by the medical physicist:
      %ofprescribed=(DFXTX0)×100


      Where DF=0.5t/159.6 is the decay factor with half-life T1/2 = 6.65 days = 159.6 h, and t is the time between the exposure rate measurements at time of expected and actual administrations in hours. The percentage of prescribed activity is required to be >80% per NRC regulations regarding medical events (

      NRC, U.S., 10 CFR Part 35 Available at: https://www.nrc.gov/reading-rm/doc-collections/cfr/part035/full-text.html.Accessed December 31, 2019.

      ), ideally ≥ 90% per institutional policy.

      Release of patient

      There are no specific exposure rate or administered activity guidelines specified by the NRC for release of patients receiving 177Lu. Thus, the exposure rate limit for release of an individual receiving radiopharmaceutical therapy under 10 CFR 35.75 was based on Eq. B-1 in NUREG 1556 Volume 9 Revision 2 Appendix U Supplement B (
      • Howe D.B.
      • Beardsley M.
      • Bakhsh S.
      NUREG-1556 Consolidated Guidance about Materials Licenses: Program-specific Guidance about Medical Use Licenses, O.o.F.a.S.M.a.E.M. Programs.
      ):
      X˙<500mrem34.6TpE


      where Tp = 6.65 days is the physical half-life, and E = 0.25 is the occupancy factor for radionuclides with Tp > 1 day and no consideration of biological elimination. Therefore, for patients receiving 177Lu, the exposure rate at 1 m should be X˙<8.6mR/h. For the case of a standard 200 mCi (Q0) Lutathera administration, the estimated exposure rate at 1 m assuming Γ = 0.181 R-cm2/mCi-h (
      • Smith D.S.
      • Stabin M.G.
      Exposure rate constants and lead shielding values for over 1,100 radionuclides.
      ) is:
      X˙=ΓQ0(100cm)2=3.6mR/h


      which is less than the required limit 8.6 mR/h for immediate release of patients. Therefore, Lutathera patients should be immediately releasable with instructions, according to NRC regulations. Patients were surveyed immediately after administration of the Lutathera to document them as being released from radiation control and provided radiation safety instructions, though they were obligated to stay for the remainder of amino acid infusion. Another survey measurement is taken after completion of amino acids and 1 h of monitoring (time of discharge). This second measurement verifies that the exposure rate from the patient is decreasing from both biological clearance and physical decay. If this reading is not decreasing significantly, then this may indicate poor biological clearance and potential nephrotoxicity. The patient's belongings are also surveyed to ensure they are free from contamination before returning them to the patient.

      Release of posted areas

      After patient discharge, the radiation safety team is contacted to clear the area of all coverings and postings and decontaminate as needed. Any items above background levels are held for decay (10 half-lives) and then re-surveyed and disposed of in regular waste if they reach background levels. Any contaminated areas are spot-cleaned with a foaming cleanser, for example, Scrubbing Bubbles (SC Johnson & Son, Inc., Racine, WI) until the survey reaches background levels. Once an area has been thoroughly surveyed and decontaminated, it is released for clinical use.

      Patient accrual

      Adult patients (age 18+) with midgut NET were initially treated on an IRB-approved EAP to receive Lutathera. At the completion of the EAP, patients were treated as per standard of care and their treatments reviewed retrospectively per a separate IRB-approved study (201811113). Assayed activities, infusion time, percentage of prescribed activity, exposure rate at release and discharge, and acute toxicities were recorded for these patients.

      FMEA analysis

      As described in Task Group-100 Report, a workflow risk-assessment was performed via FMEA, which included designing a process map, identifying potential failure modes, and ranking of these different failure modes. Failure modes were identified by the team as instances leading to wrong dosage (activity) and/or radioactive contamination. Team members scored failure modes by assigning numerical values from 1 to 10 for occurrence, severity, and lack of detectability per Task Group-100 Report. Team members were provided Table 2 from Task Group-100 when ranking failures related to wrong dosage, and the following when ranking failures related to contamination from 1 to 10, with:
      ≥Level 2 = minor decontamination
      ≥Level 5 = moderate decontamination
      ≥Level 9 = major decontamination (i.e., requiring shutdown of the facility for >24 h and reporting to NRC).
      The median of each of the occurrence, severity, and lack of detectability scores was then multiplied together to obtain the risk priority number (RPN) value for each failure mode with higher RPN values indicating higher risk.

      Results

      We present our findings for 22 patients receiving Lutathera: 11 patients were part of an EAP and 11 patients were post-EAP. Between 03/2017 and 04/2018 (before FDA approval), 11 of these patients were enrolled in an IRB-approved EAP, accounting for 36 administrations (Table 1). The treatment with a maximum exposure rate reading of 4.1 mR/h at release (see Table 1) had a pretreatment vial reading of 3.76 mR/h at 1 m, which suggests that the post-Lutathera release measurement was likely inadvertently measured at a distance <1 m. The treatment with a 177Lu infusion time of 65 min (see Table 1) was using the gravity infusion method (
      • Hromadik L.K.
      • Sturges L.
      Caring for patients receiving 177Lu-dotatate, Lutathera®: a treatment of Hope for patients with gastroenteropancreatic neuroendocrine tumors.
      ), which is slower and more cumbersome than an IV-infusion pump, and before implementing the repeat survey readings of the vial for completing administration.
      Table 1Results from Lutathera administrations on EAP (n = 36)
      QuantityMean (range)
      Difference between assayed vs manufacturer's activities−3.6% (−6.1% to 1.4%)
      Lutathera infusion time36.9 min (26 to 65 min)
      Delivered vs prescribed activities97.1% (89.5 to 99.4%)
      1 m exposure rate reading at completion of activity infusion1.87 mR/h (0.95 to 4.1 mR/h)
      1 m exposure rate reading at patient discharge0.94 mR/h (0.43 to 1.82 mR/h)
      All 11 patients (61% of administrations) under the EAP had Grade 1 (G1) nausea, and 5/11 patients (23% of administrations) experienced G1–G2 emesis despite premedication with antiemetics (Fig. 4a/c). Two of six peripheral IV-line complications resulted in undeliverable dose.
      Figure thumbnail gr4
      Fig. 4Fractions (%) with G0–G2 acute toxicities for Lutathera patients when administered commercial amino acids (a/c) vs local pharmacy amino acids (b/d).
      After the EAP, 11 patients (44 administrations) were treated between 06/2018 and 02/2019 with a revised amino acid formulary and peripherally inserted central catheter (PICC) line. The revised amino acid formulary contained only lysine and arginine instead of the 20 total amino acids found in Clinisol 15%. These administrations were analyzed for PICC-line complications and acute toxicity. A total of 7/11 patients (27% of administrations) had G1–G2 nausea, 3/11 patients (7% of administrations) had G1–G2 emesis without premedication, and none had PICC line complications (see Fig. 4b/d).
      Across all administrations, there was minimal radiation contamination and all examination rooms and hallways were considered releasable after patient discharge and decontamination, if necessary. The area of highest contamination was often the bathroom, especially under the toilet seat. However, with the use of a foaming cleanser, the radiation safety team was able to decontaminate the area to background levels for release before the next day.

      FMEA

      A total of 13 team members participated in the FMEA (≥2 each of radiation therapists, authorized users, radiation safety staff, medical physicists, and nurses). Results of the FMEA are described in Table 2 and Supplement Fig. 2. Preparation of the amino acids (Step 2) had the highest risk priority number (162), and Radiopharmaceutical Delivery (Step 15) had the highest number of failure modes (total of 10). In Table 2, the five highest risk priority numbers and their associated failure modes were (highest to lowest): (1) error in preparing amino acid formulation, (2) laboratories not checked, (3) release instructions not clear to patient, (4) not checking status of/or preparing for patient incontinence, (5) improper initial survey of vial for administered activity calculation.
      Table 2Median occurrence, severity, and detectability scores for failure modes from the FMEA
      Step descriptionPotential failure modesMedian occurrenceMedian severityMedian detectabilityRisk priority number
      • 1.
        Scheduling/ordering (RTT/MD)
      Missed order (i.e., forgotten, email not sent, etc.)3.03.02.018
      Wrong date2.03.02.012
      Wrong facility1.03.02.06
      Wrong patient1.02.52.05
      Labs not checked4.05.07.0140
      Written directive incomplete/missing2.04.02.016
      Consent not obtained3.52.53.026
      • 2.
        Amino acid prep (pharmacy)
      Error in preparing amino acid formulation2.09.09.0162
      • 3.
        Receiving/delivery (RS)
      Wrong delivery date (or late delivery)2.04.02.016
      Delivered to wrong location/facility2.03.02.012
      Damaged packaging2.05.02.020
      Radioactive contamination on packaging2.03.02.012
      Not entered in RAM inventory properly2.02.03.012
      • 4.
        Source check-in (MP)
      No patient identifying info2.02.01.04
      Radioactive contamination on packaging2.03.51.511
      Damaged vial1.56.51.515
      Wrong activity (measured incorrectly or dosage from company incorrect)2.06.52.026
      Recalled dose from manufacturer2.04.01.512
      Improper initial survey of vial for administered activity calculation3.08.03.072
      • 5.
        Area prep (RS)
      Missed papering/covering area1.52.52.08
      Admin chairs not brought into examination rooms1.02.01.02
      Foot covers and waste bins not set out1.53.02.09
      Stanchions not set out (area not visibly restricted)1.52.51.04
      Radiation room signage/notices not displayed1.52.02.06
      Patient/visitor instructions not displayed1.52.01.03
      • 6.
        Amino acid time-out (NS)
      Wrong patient1.010.01.010
      Wrong treatment1.010.01.010
      Not checking status of, or preparing for patient incontinence4.56.53.088
      Not checking status of dose (arrived, correct, ready for treatment)2.54.52.023
      • 7.
        Cart prep (RTT)
      Admin cart improperly prepared for infusion2.02.52.010
      Admin cart improperly prepped for contamination2.03.02.012
      Patient packet with release instructions not brought to treatment2.02.52.010
      Checklist not brought to treatment2.03.01.59
      • 8.
        Check Amino Acid labels/saline bags (NS)
      Label Amino Acid of bag not checked for correct formula2.07.02.535
      Amino Acid bag not scanned and verified2.06.52.533
      Wrong size of saline bag for flushing2.52.51.59
      • 9.
        Exchange clothing for hospital gown (NS)
      Patient not changed out of their street clothes into paper/disposable clothing2.03.01.59
      Patient belongings not properly stowed away2.03.01.59
      • 10.
        Prime lines (NS)
      Proper placement of lines not checked (IV or PICC)2.57.53.056
      Lines not primed and checked for flow2.07.03.042
      • 11.
        Amino acid admin (NS)
      Patient status of nausea/emesis, etc not checked or not prepared for2.02.52.010
      Not verified that lines were primed3.06.02.036
      Dose line not primed2.07.02.028
      Wrong infusion rate2.05.02.020
      Start time not recorded/wrong infusion time3.03.02.018
      • 12.
        Pre-radiopharm prep (RTT)
      Patient not instructed to void before admin3.03.02.018
      Absorbent paper not placed under patient's arm, floor, chair, cart, and between cart and patient3.03.52.021
      Patient's arm not positioned at height below vial3.54.02.028
      Initial survey not performed1.53.52.011
      • 13.
        Radiopharm time-out (RTT/MD)
      Not verify that lines were primed1.57.02.021
      Wrong patient1.08.01.08
      Wrong dose/vial2.07.01.521
      Wrong radionuclide1.09.01.514
      Wrong route1.09.01.09
      Wrong site1.09.01.09
      • 14.
        Contamination control (RTT)
      Missing survey/contamination equipment by stanchions2.03.02.012
      Personnel protection equipment not worn or incomplete (no goggles, double-gloves, etc).3.54.02.028
      Inadequate restriction of traffic (not monitoring PPE of folks entering or surveying when leaving)3.53.53.037
      • 15.
        Radiopharm deliver (RTT/MD)
      Amino Acids not delivered for >30 min before radiopharm admin2.07.02.028
      Wrong infusion rates for Luta (programmed wrong, too slow, too fast)2.06.02.024
      Level of fluid in vial not checked during infusion2.07.52.030
      No monitoring for extravasation, discomfort of patient2.07.53.045
      Not monitoring for IV line occlusion2.07.02.535
      Flow of Amino Acid stopped2.06.52.026
      No monitoring or incorrect monitoring of exposure rate of vial vs patient2.05.53.033
      Not administering drug for a minimum amount of time (at least 20 min)1.05.01.05
      Delivering drug for period > 30 min2.04.51.09
      May not have delivered maximum activity (activity still in lines)2.07.03.549
      • 16.
        Patient release survey (RTT)
      Not measured at 1 m2.03.03.018
      High background or contaminated items present2.54.53.034
      Survey meter daily QA not performed (faulty survey meter)1.54.04.024
      Release survey measurement not documented properly2.55.03.038
      Patient release not documented properly (i.e., specify no instructions vs instructions)3.03.53.032
      Patient not given release instructions3.54.03.042
      Release instructions not clear to patient4.07.03.598
      • 17.
        Measure residual and calculate administered activity (MP)
      Not all items placed in Nalgene2.04.03.024
      Improper measurement of residual (e.g., not measured at 30 cm, not rotated to find max reading, survey meter different from that used for initial measurement)2.05.03.030
      • 18.
        Disposal of contaminated items (RTT)
      Contaminated items placed in regular waste2.06.03.036
      Staff not surveyed prior to leaving room2.06.03.542
      Cart not surveyed for contamination2.06.04.554
      • 19.
        Patient monitoring (NS)
      Not asking patient about nausea and lightheadedness1.03.02.58
      Not checking patient BP and heart rate1.06.01.06
      • 20.
        Removal of IV line (MD/NS/RTT)
      Improper disconnection of lines2.05.02.020
      • 21.
        Patient discharge (RTT/NS)
      Survey not done or not properly measured at 1 m2.03.03.018
      Belongings not surveyed or improperly surveyed before discharge3.03.53.032
      • 22.
        Decontamination/room release (RS)
      Admin room not decontaminated properly2.06.53.039
      Bathroom not decontaminated properly2.06.53.039
      Room release survey not performed2.06.53.039
      • 23.
        Waste disposal/decay in storage (RS)
      Not all radioactive waste collected2.05.03.030
      Not labeled properly2.02.52.513
      RAM inventory not matched/cleared properly (i.e., cradle-to-grave tracking)2.03.02.012
      Not held for decay for appropriate time2.05.03.030
      Waste not stored properly2.03.02.515
      Not surveyed for final disposal properly2.05.02.525
      Staff with the associated responsibility include the following: Physician/Authorized User (MD), Radiation Therapy Technologist (RTT), Nursing Staff (NS), Radiation Safety (RS), and Medical Physicist (MP). Failure modes with the five highest risk priority numbers are highlighted.

      Discussion

      To our knowledge, this is the only published experience of delivering Lutathera radiopharmaceutical therapy specifically in the outpatient radiation oncology department setting. Recently, Abbott et al. reported their procedures and experience in a Nuclear Medicine setting (
      • Hromadik L.K.
      • Sturges L.
      Caring for patients receiving 177Lu-dotatate, Lutathera®: a treatment of Hope for patients with gastroenteropancreatic neuroendocrine tumors.
      ). Furthermore, Hope et al. reported the NANETS/SNMMI procedures for Lutathera administration, specifically in nuclear medicine or oncology infusion clinics (
      • Hope T.A.
      • Abbott A.
      • Colucci K.
      • et al.
      NANETS/SNMMI procedure standard for somatostatin receptor-based peptide receptor radionuclide therapy with (177)Lu-dotatate.
      ). However, Hope et al. and Abbott et al. (
      • Hope T.A.
      • Abbott A.
      • Colucci K.
      • et al.
      NANETS/SNMMI procedure standard for somatostatin receptor-based peptide receptor radionuclide therapy with (177)Lu-dotatate.
      ,
      • Abbott A.
      • Sakellis C.G.
      • Andersen E.
      • et al.
      Guidance on (177)Lu-dotatate peptide receptor radionuclide therapy from the experience of a single nuclear medicine division.
      ) do not specifically address unique clinical scenarios that the administering team may encounter or how to administer this radiopharmaceutical therapy in clinic rooms that are not purposed for nuclear medicine procedures. For example, we found that with the existing construction of our examination rooms, no modification, such as additional shielding, was needed. The content of this article can provide guidance for the administration of Lutathera in academic and community radiation oncology departments. Lessons we learned during the EAP and beyond have led to procedural modifications including use of PICC lines, in-house amino acid formulary, and a written procedural checklist, increasing our throughput from 1 to 4 patients per day.

      Infusion

      As a result of our initial experience with peripheral IV-infusion of Lutathera and undeliverable dosages, our practice was changed after the EAP so that all patients receive PICC lines the day before infusion. To date, no other institutional experience has reported the use of PICC as standard access for their patients. These data, although not specifically designed to prospectively assess safety of PICC access Lutathera administration, demonstrate no high toxicity to indicate concern with central access administration.
      Initial training from the vendor and experience from others suggest using the gravity infusion method. We attempted this with our first few patients but found it time consuming and cumbersome (
      • Hope T.A.
      • Abbott A.
      • Colucci K.
      • et al.
      NANETS/SNMMI procedure standard for somatostatin receptor-based peptide receptor radionuclide therapy with (177)Lu-dotatate.
      ,
      • Hromadik L.K.
      • Sturges L.
      Caring for patients receiving 177Lu-dotatate, Lutathera®: a treatment of Hope for patients with gastroenteropancreatic neuroendocrine tumors.
      ). We then transitioned to using a programmable infusion pump instead for administration, similar to that suggested by Hope et al. (
      • Hope T.A.
      • Abbott A.
      • Colucci K.
      • et al.
      NANETS/SNMMI procedure standard for somatostatin receptor-based peptide receptor radionuclide therapy with (177)Lu-dotatate.
      ,
      • Hromadik L.K.
      • Sturges L.
      Caring for patients receiving 177Lu-dotatate, Lutathera®: a treatment of Hope for patients with gastroenteropancreatic neuroendocrine tumors.
      ). This is now our standard infusion method.
      As described in the administration checklist (Supplementary Materials), priming of the saline line is critical for proper administration. In the event of a saline line not being primed before insertion into vial, air will push undiluted Lutathera into the patient. Removal of the short saline needle for priming and reinsertion can lead to diminished seal and inability to deliver the prescribed activity. In our clinic, we detach the hub of the needle from the IV-line and then prime the line with saline. When primed, the line is reconnected to the short needle and saline infusion restarted. Verbal acknowledgment of line priming was added to our checklist after an incident where the line necessitated engineering this work around.
      If the Lutathera level rises during infusion, air can be infused into the vial with a syringe to depress the level. This will allow continual administration without stopping the infusion. Caution should be exercised so that air is not inadvertently pushed directly into the patient line.
      Initially, activity was administered until survey measurements of the vial reached low levels. However, owing to interference from patient or residual in the vial/line, these measurements often did not fully reach background levels. This resulted in unnecessarily long infusion times. We eventually implemented a three consecutively stable readings approach, which has reduced infusion times by approximately 30 min.

      Contamination control

      Patients that are incontinent of urine or unable to readily maneuver to the bathroom were catheterized with Foleys before Lutathera administration. To prevent contamination of treatment chairs, plastic liners in addition to absorbent paper were placed under the chair linen coverings to catch unanticipated spills. These procedures were implemented after a catheterized patient's Foley leaked and soaked through the chair cover, resulting in a contaminated chair. The chair was out of clinical service for 1 month to allow for decay to background levels. Similarly, soiled linen is stored as radioactive waste and allowed to decay before disposal.
      Currently, the only area that significantly demonstrates consistent contamination is the restroom, particularly underneath the toilet seat, as expected from renal excretion (
      • Calais P.J.
      • Turner J.H.
      Radiation safety of outpatient 177Lu-octreotate radiopeptide therapy of neuroendocrine tumors.
      ,
      • Bodei L.
      • Buxbaum S.
      • Rodrgues M.
      • Bodei L.
      • Mueller-Brand J.
      • Baum R.P.
      • et al.
      The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours.
      ). However, we have never had to restrict access to a bathroom longer than overnight. In these cases, allowing the cleaning solution to work overnight on the surface and additional cleaning the next morning was successful in removing the contamination that penetrated the pores of the toilet surface, enough for radiation levels to be at background and be considered “releasable.”

      Toxicity control

      The significant nausea associated with the commercial amino acid infusion motivated our team to establish a formulary solution with the minimal requirements for kidney protection (
      • Strosberg J.
      • El-Haddad G.
      • Wolin E.
      • et al.
      Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors.
      ). The in-house solution resulted in significant decreased nausea and anti-emetic use. This decreased the risk of contamination and allowed shortening post-treatment observation from 1 h to 30 min.
      Should the radiation safety team note that the dedicated bathroom toilet or urinal is not as radioactive as expected, immediate attention should be directed to the amino acid preparation. Failure to administer amino acids or incorrect formulation may result in poor renal excretion and nephrotoxicity. Survey of the bathroom may function as a crude surrogate of renal excretion.

      Unanticipated hospitalizations

      In a few situations, the patients were discharged to the emergency department due to G2 emesis or tachycardia to receive further treatment. As described, even immediately after amino acid infusion, the patients are considered “releasable with instructions” according to NRC regulations. Therefore, although universal precautions are sufficient in interactions with these patients, patients were instructed to share their instructions with the personnel in the emergency department and to contact the radiation oncology department with further questions. Owing to concerns from emergency department staff about exposure to radiation, physicians now include statements in their procedure notes attesting to the releasability of the patient to the general public and include the phone number for the radiation safety team to answer any questions.

      FMEA

      This is the first FMEA completed for Lutathera radiopharmaceutical therapy. Our FMEA was completed based on our process map after our initial 2-year experience. Error in preparing the amino acid formulary had the highest RPN, with scores reflecting high severity and low detectability. The wrong amino acid formulary could result in significant nephrotoxicity and, unfortunately, is nearly impossible to detect until administered to the patient. Our two post-administration patient surveys and post-discharge restroom survey may help detect the wrong amino acid formulary if it is not clearing from the patient appropriately. The remaining highest scoring failure modes pose the risk of either nephrotoxicity and/or contamination of clinic/public areas. This includes release instructions not clear to the patient. Levart et al. found that without proper distancing and contact restrictions between the patient and his or her partner, dose to the partner could be 0.24–2 rem (
      • Levart D.
      • Kalogianni E.
      • Corcoran B.
      • et al.
      Radiation precautions for inpatient and outpatient (177)Lu-DOTATATE peptide receptor radionuclide therapy of neuroendocrine tumours.
      ). This further emphasizes the importance of the patient both receiving and understanding the release instructions so they can practice proper distancing from other individuals and reduce their exposure from the patient. In general, the processes we have in place, particularly a checklist (Supplementary Materials), make nearly all failure modes relatively easy to detect (see Table 2 and Supplement Fig 2).

      Limitations

      Some limitations with this study included the application of the FMEA. Table 2 in AAPM's Task Group 100 Report was initially designed for external beam radiation therapy treatments. Therefore, some of the scoring metrics and corresponding descriptions may not directly translate over to a radiopharmaceutical therapy application. However, we believe the descriptions in Task Group 100 Report's Table 2 are generalized enough adapt it to radiopharmaceutical therapy processes. Another limitation is the inherent skillset limitation in performing the FMEA with such a complex, multidisciplinary treatment procedure. Some participants may not be as knowledgeable with specific failure modes if the related task is outside their skillset. We asked FMEA participants to not score a failure mode if they were not familiar enough with the related task to provide it an educated score. We also did our best to include at least two participants from each discipline (e.g. two nurses, two radiation oncologists, three radiation therapists, three physicists, and three radiation safety team members) to provide enough data for the analysis and limit bias. However, a more thorough FMEA would have included more participants.

      Conclusion

      With careful planning of technical and logistical considerations as outlined here, Lutathera radiopharmaceutical therapy can be implemented in the outpatient radiation oncologic clinic setting, enabling radiation oncologists to provide this therapeutic option to patients with advanced midgut NETs.

      Supplementary data

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