SPECIAL CONTRIBUTION

NANETS/SNMMI Procedure Standard for Somatostatin

Receptor–Based Peptide Receptor Radionuclide Therapy
with 177Lu-DOTATATE
Thomas A. Hope1,2, Amanda Abbott3, Karen Colucci4, David L. Bushnell5,6, Linda Gardner7, William S. Graham1,
Sheila Lindsay8, David C. Metz9, Daniel A. Pryma10, Michael G. Stabin11, and Jonathan R. Strosberg12
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California; 2Department

of Radiology, San Francisco VA Medical Center, San Francisco, California; 3Dana-Farber Cancer Institute, Boston,
Massachusetts; 4Lehigh Valley Health Network, Allentown, Pennsylvania; 5Department of Radiology, Carver College of Medicine,
University of Iowa, Iowa City, Iowa; 6Iowa City VA Medical Center, Iowa City, Iowa; 7Department of Nuclear Medicine, University
of California, Los Angeles, Los Angeles, California; 8Division of Hematology/Oncology, Department of Medicine, University of
California, San Francisco, San Francisco, California; 9Division of Gastroenterology, Department of Medicine, Perelman School
of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; 10Division of Nuclear Medicine & Clinical
Molecular Imaging, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia,
Pennsylvania; 11NV5/Dade Moeller, Richland, Washington; and 12Department of Gastrointestinal Oncology, Moffitt Cancer
Center, Tampa, Florida

scientific and professional organization founded in 1954 to promote

With the recent approval of 177Lu-DOTATATE for use in gastroen- the science, technology, and practical application of nuclear medicine.
teropancreatic neuroendocrine tumors, access to peptide receptor In addition to publishing journals, newsletters, and books, the SNMMI
radionuclide therapy is increasing. Representatives from the North also sponsors international meetings and workshops designed to
American Neuroendocrine Tumor Society and the Society of Nu- increase the competencies of nuclear medicine practitioners and to
clear Medicine and Molecular Imaging collaborated to develop a
promote new advances in the science of nuclear medicine.
practical consensus guideline for the administration of 177Lu-
This collaboration between NANETS and SNMMI aims to
DOTATATE. In this paper, we discuss patient screening, mainte-
nance somatostatin analog therapy requirements, treatment location define new procedure standards for peptide receptor radionuclide
and room preparation, drug administration, and patient release as therapy (PRRT) to improve the quality of service to patients. Existing
well as strategies for radiation safety, toxicity monitoring, manage- practice guidelines will be reviewed for revision or renewal as
ment of potential complications, and follow-up. Controversies re- appropriate, on their fifth anniversary or sooner, if indicated. Each
garding the role of radiation dosimetry are discussed as well. This practice standard has undergone a thorough consensus process in
document is designed to provide practical guidance on how to safely which it has been subjected to extensive review. Much of the
treat patients with this therapy.
content within the guidelines are based on working group experi-
J Nucl Med 2019; 60:937–943 ence. These procedure standards are intended to assist practitioners
DOI: 10.2967/jnumed.118.230607 in providing appropriate nuclear medicine care for patients. They
are not inflexible rules or requirements of practice and are not
intended, nor should they be used, to establish a legal standard of
care. For these reasons and those set forth below, NANETS and
PREAMBLE SNMMI caution against the use of these guidelines in litigation
in which the clinical decisions of a practitioner are called into
The present guidelines/standards were developed collaboratively question. The ultimate judgment regarding the propriety of any
by the North American Neuroendocrine Tumor Society (NANETS)
specific procedure or course of action must be made by medical
and the Society of Nuclear Medicine and Molecular Imaging
professionals taking into account the unique circumstances of
(SNMMI). NANETS is a multidisciplinary professional society of
each case. Thus, there is no implication that an approach differing
neuroendocrine specialists in North America that was founded in
from the guidelines, standing alone, is below the standard of care.
2005. NANETS’s mission is to improve neuroendocrine tumor
To the contrary, a conscientious practitioner may responsibly
disease management through increased research and educational
opportunities. NANETS is committed to a multidisciplinary approach adopt a course of action different from that set forth in the
and consists of doctors and scientists involved in different specialties guidelines when, in the reasonable judgment of the practitioner,
of neuroendocrine tumors (NETs). The SNMMI is an international such course of action is indicated by the condition of the patient,
limitations of available resources, or advances in knowledge or
technology subsequent to publication of the guidelines.
For correspondence or reprints contact: Thomas A. Hope, University of The variety and complexity of human conditions make it impos-
California, San Francisco, Department of Radiology and Biomedical Imaging, sible to always reach the most appropriate diagnosis or to predict
505 Parnassus Ave., San Francisco, CA 94143.
Email: [email protected] with certainty a particular response to treatment. Therefore, it
COPYRIGHT © 2019 by the Society of Nuclear Medicine and Molecular Imaging. should be recognized that adherence to these guidelines will not

SOMATOSTATIN RECEPTOR–BASED PRRT WITH 177LU-DOTATATE • Hope et al. 937

ensure an accurate diagnosis or a successful outcome. All that SOMATOSTATIN ANALOG THERAPY
should be expected is that the practitioner will follow a reason-
SSA therapy is used frequently to treat NET patients, and SSAs
able course of action based on current knowledge, available re-
are typically administered in depot formulations every 4 wk. It is
sources, and the needs of the patient to deliver effective and safe
recommended that PRRT treatments be scheduled at least 4 wk
medical care. The sole purpose of these procedure standards is to
after the last long-acting SSA therapy to prevent interference with
assist practitioners in achieving this objective.
SSTR binding. For symptomatic patients, short-acting SSAs being
used as a bridge should be stopped at least 24 h before treatment.
BACKGROUND
Subsequent SSA doses can be administered as soon as several hours
NETs are a heterogeneous group of malignancies that frequently after the completion of the radiopharmaceutical therapy. During and
overexpress somatostatin receptors (SSTRs) (1). NETs can be im- after completion of PRRT, it is generally agreed that syndromic
aged using somatostatin analogs (SSAs) labeled with 68Ga (68Ga- patients should remain on SSA therapy. It is unclear whether patients
DOTATATE and 68Ga-DOTATOC) (2). b-emitting radionuclides with nonfunctional tumors should remain on SSA treatment regard-
such as 177Lu can be used for PRRT (3). The NETTER-1 trial less of whether or not they had progressed on SSA therapy before
demonstrated prolonged progression-free survival in midgut NET initiation of PRRT. In the NETTER-1 study, all patients remained
patients treated with 4 cycles of 177Lu-DOTATATE, which subse- on long-acting release octreotide despite prior progression on this
quently led to the approval of this therapy (4). drug, and the 177Lu-DOTATATE package insert suggests that patients
should remain on SSAs for up to 18 mo after treatment (6). How-
TREATMENT OVERVIEW ever, there are no clear data to support or refute this recommendation.
177Lu-DOTATATE is administered at an activity of 7.4 GBq
TREATMENT LOCATION
(200 mCi) every 8 6 1 wk for 4 cycles. Combined with prophy-
lactic amino acid infusions and antiemetics, each treatment visit Sites have the option to provide PRRT in an inpatient or out-
can last approximately 5–8 h (Fig. 1). Before starting PRRT treat- patient setting, within the oncology infusion clinic or nuclear med-
ments, each treatment site must ensure that 177Lu is included in their icine department, or a combination of both locations. Most sites in
institutional radioactive materials license. A detailed review of pro- the United States treat in the outpatient setting. Oncology nursing
cedures surrounding 177Lu-DOTATATE therapy is provided below. staff are often more accustomed to the complexities of required
concomitant medication infusions and patient monitoring than
PATIENT SCREENING nuclear medicine staff, but nuclear medicine staff are well
trained in radiation safety and the necessary precautions required
Patients should be evaluated by a multidisciplinary NET team,
during administration of radioactivity. If a combination approach
including a cancer specialist with expertise in the medical man-
is taken (i.e., the patient is transported between departments for
agement of NETs as well as a nuclear medicine physician or
specific components of the procedure), extra caution regarding
appropriate authorized user to decide on the appropriateness and
radiation protection is required for patient travel. When treated
timing of PRRT in individual patients. Potential candidates should
as an outpatient, a patient should be forewarned of the uncommon
undergo an SSTR PET scan or SSTR scintigraphy (111In-pentetreotide)
possibility of an overnight hospital stay should a complication such
to demonstrate adequate SSTR expression (2). Traditionally, SSTR
as a neuroendocrine hormonal crisis or severe emesis occur (6).
expression on 111In-pentetreotide greater than background hepatic
uptake has been considered an eligibility requirement for PRRT
ROOM PREPARATION
(5). Necessary levels of SSTR expression on 68Ga-based SSTR
PET have not been clearly defined, but lesion uptake should ex- Because body fluids (primarily urine) are radioactive after 177Lu-
ceed background hepatic uptake. Laboratory values should be DOTATATE administration, room preparation is essential to reduce
checked shortly before the treatment is ordered (typically 2 wk potential contamination. For example, patient stretchers, chairs,
before each cycle). These should include blood urea nitrogen, floors, and lower walls can be covered with a prophylactic protective
creatinine, albumin, alkaline phosphatase, aspartate aminotrans- covering (Fig. 2). Furthermore, whereas a treatment suite with an
ferase, alanine aminotransferase, total bilirubin, white blood cell
with differential, hemoglobin, and platelet counts. The threshold TABLE 1
values provided in Table 1 should be taken as general eligibility Recommended Laboratory Thresholds for PRRT Treatment
guidelines for therapy.
Acceptable value before
Laboratory first treatment

Hemoglobin (HGB) .8 g/dL

White blood cell count (WBC) .2K/mm3
Platelet count (PLT) .70K/mm3
Estimated glomerular filtration .50 mL/min
rate (eGFR)
Total bilirubin #3 · ULN
Serum albumin .3.0 g/dL
FIGURE 1. Timeline of administration of antiemetics, amino acids, and
177Lu-DOTATATE during PRRT. Antiemetics can be repeated during
ULN 5 upper limits of normal.
amino acid infusion as needed.

938 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 60 • No. 7 • July 2019

 with the 177Lu-DOTATATE, and continue
at 320 mL/h or greater until the total vol-
ume has been administered. Commencing
at a low rate of 100 mL/h for the high-
concentration amino acid solution and in-
creasing slowly (e.g., by 20–50 mL/h every
15–20 min) has been somewhat successful
at reducing side effects relating to nausea or
vomiting.
An alternative compounded amino acid
formulation consisting solely of 25 g of
lysine and 25 g of arginine diluted in 1 L of
FIGURE 2. Example room preparation for therapy. A dedicated bathroom should be used and normal saline for injection should be con-
wrapped in order to prevent urine contamination. sidered (8). The compounded 2-amino-acid
solution is substantially less emetogenic
and can generally be infused over a shorter
attached toilet is ideal, having a dedicated toilet nearby is accept- period of time. The use of arginine–lysine formulations may be
able as the patient will need to void frequently on the completion preferred due to improved tolerability; however, due to licensing
of the 177Lu-DOTATATE infusion and may need assistance. Local requirements and compounding regulations, compounded arginine–
rules related to radioactive waste materials should be followed lysine formulations may not be available at many institutions. When
under the guidance of a local radiation safety officer. using the compounded arginine–lysine solution, it should be infused
at a rate of 250 mL/h for 4 h, commencing 30 min before the
PATIENT PREPARATION treatment with the radiopharmaceutical.
It may be helpful to have patients change into hospital scrubs or
gowns on arrival in order to avoid potential contamination of personal ANTIEMETIC MEDICATIONS
belongings. If stress urinary incontinence is a concern, disposable Nausea and vomiting are common during the administration of
undergarments are also recommended. For some patients, a Foley commercial amino acid solutions when infusion rates are above
catheter with acrylic shielding of the Foley bag may be necessary. 250 mL/h. Therefore, it is recommended to use an intravenous
However, routine bladder catheterization is not recommended. premedication regime consisting of a 5-HT3 antagonist (e.g.,
A peripheral vein in the antecubital fossa is the preferred loca- granisetron, ondansetron, or palonosetron), an NK1 receptor antag-
tion for venous access, and intravenous lines in both arms are onist (e.g., fosaprepitant), and an H2 receptor antagonist (e.g.,
preferred, one to administer the radioactivity and one to administer famotidine). When increasing the amino acid rate to the
the amino acid solution. If 2 lines are not possible, the amino acids target of 320 mL/h, additional doses of the 5-HT3 antagonist
and radiotherapy may be infused through the same line. Central lines may be required with the addition of a D2 receptor antagonist (e.g.,
may be used for the administration of the premedications and the prochlorperazine). Benzodiazepines may also be required for antic-
amino acid solution in the case of patients with difficult peripheral ipatory nausea and vomiting (9). Steroids, such as dexamethasone,
venous access; however, a peripheral line is the recommended route can also be administered after infusion of 177Lu-DOTATATE.
for the administration of the 177Lu-DOTATATE infusion, as the Additionally, cooling and pressure aids may also be benefi-
use of a central line has not been studied. Intermittent assessment cial to help with the possible side effects of the amino acid solution
of ongoing vascular access is necessary throughout the procedure infusion. Patient education is highly important at the beginning of
due to the high osmolarity of the amino acid solutions, and local the procedure to ensure the patient understands the importance of
reactions at the infusion site may occur. Additionally, patency of where and how to contain emesis under these circumstances.
the peripheral intravenous site should be monitored continuously Patients receiving compounded arginine–lysine generally require
throughout the infusion of the 177Lu-DOTATATE. only a 5-HT3 antagonist as prophylactic medication.

AMINO ACID SOLUTIONS RADIOPHARMACEUTICAL ADMINISTRATION

Administration of an amino acid solution with the appropriate Treatment centers can choose among different infusion methods
lysine and arginine concentration (Table 2) before, during, and for 177Lu-DOTATATE administration, including the gravity method,
after the 177Lu-DOTATATE infusion is required to decrease reab-
sorption of 177Lu-DOTATATE via the proximal renal tubules and TABLE 2
thereby decrease the radiation dose to the kidneys (7). Several high- Content Requirements for the Amino Acid Solution
concentration commercial amino acid solutions are currently avail-
able with the correct concentration of arginine and lysine (Table 3); Item Specification
however, they also include additional amino acids, which raise the
osmolality of the solution and are associated with significant nausea Lysine HCl content Between 18 and 24 g
and vomiting during infusion. The target infusion rate of the com- Arginine HCl content Between 18 and 24 g
mercial amino acid solutions should reach 320 mL/h. 177Lu-DOTA- Volume 1.5 to 2.2 L for commercial
TATE should generally not be administered until this rate is reached (1.0 L for compounded)
or until one eighth of the total volume of amino acid solution has
Osmolarity ,1,050 mOsmol
been infused. The amino acid solution should infuse concurrently

SOMATOSTATIN RECEPTOR–BASED PRRT WITH 177LU-DOTATATE • Hope et al. 939

 TABLE 3
Currently Available Commercial Amino Acid Solutions

Formulation Amino acid concentration Dilution

Aminosyn II 10% 21 g of lysine, 20.4 g of arginine in 2 L

Aminosyn II 15% 23.6 g of lysine, 22.9 g of arginine in 1.5 L Dilute to approximately 2 L
Clinisol 15% 18 g of lysine, 18 g of arginine in 1.6 L Dilute to approximately 2.2 L
Plenamine 15% 18.8 g of lysine, 23.5 g of arginine in 1.6 L Dilute to approximately 2.1 L
Trophamine 10% 18 g of lysine, 26 g of arginine in 2.2 L Consult*
Premasol 10% 16.4 g of lysine, 24 g of arginine in 2 L Consult*

*Consult with treating physician as lysine–arginine concentration may be outside specifications, which may increase adverse events.

the saline infusion method, the pump method with a vial, and the DOSAGE MODIFICATIONS FOR ADVERSE REACTIONS
pump method with a syringe (Fig. 3) (6). Supplemental Table 1
In patients who have baseline renal, liver, or bone marrow
(supplemental materials are available at http://jnm.snmjournals.org)
dysfunction, or in those who develop toxicity while on treatment,
provides step-by-step instructions for each method (10). The saline modification of the administered 177Lu-DOTATATE activity can
infusion method may result in leakage from the vial, and care be considered (6). In patients with preexisting toxicity, decreased
should be taken to prevent contamination. The pump method with administered activity or longer intervals between administrations
a syringe can result in extra radiation exposure to the technologists can be considered. Bone marrow toxicity is the most common
when drawing the activity from the vial and higher residual values. adverse event to develop during treatment. In patients experienc-
The pump method with the vial requires the availability of an ing myelosuppression greater than grade 1, one can delay treat-
automated infusion pump. Regardless of the method used, one should ment, allowing bone marrow function to recover, administer a lower
use appropriate radiation shielding and aseptic technique when pre- administered activity (i.e., 3.7 GBq [100 mCi]) during the next
paring and administering the radiopeptide solution, including wearing treatment, or permanently stop therapy. Oftentimes, thrombocy-
appropriate personal protective equipment, using tongs when han- topenia will resolve with a delay. Renal and liver toxicity rarely
dling the vial to minimize radiation exposure, confirming the amount occur during treatment, but if patients develop toxicity that is
of the radioactivity of the radiopeptide vial (and syringe if applicable) attributable to 177Lu-DOTATATE (e.g., elevated bilirubin or re-
with an appropriate dose calibrator before administration, and duction in kidney function), therapy should be withheld until tox-
inspecting the product visually for particulate matter and discolor- icity resolves. Because of issues related to differential reimbursement
ation under a shielded screen (the vial should not be used if partic- based on the administered activity, it may be difficult to administer at
ulates or discoloration are present). The therapy dosage should be half the normal activity. Therefore, it may only be feasible to
administered over 30 min and should not be administered as a bolus. prolong the delay between treatments.

PATIENT MONITORING AND

POTENTIAL REACTIONS

Hormonal Crisis (Carcinoid Crisis)

Neuroendocrine hormonal crises due to
excessive release of hormones or bioactive
substances develop in 1% of patients and
typically occur during treatment or within
2 d after the initial treatment (6,11). Typ-
ical clinical manifestations include cutane-
ous flushing, diarrhea, bronchospasm, and
hypertension. Hormonal crises can be
treated with intravenous high-dose SSAs,
intravenous fluids, corticosteroids, and cor-
recting of electrolyte disturbances in patients
with diarrhea or vomiting. Pretreating patients
at high-risk for crisis has been suggested, al-
though this is not done at most centers (12).

Infiltration of 177Lu-DOTATATE

Prevention of infiltration is critical and

FIGURE 3. Administration techniques. (A) Gravity method. (B) Pump method with vial. (C) Pump includes testing the intravenous line patency
method with syringe. Please see Supplemental Table 2 for further details on the administration before administration of the radiopharma-
techniques. ceutical, direct observation of the site during

940 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 60 • No. 7 • July 2019

the administration, and rapid intervention if swelling or pain develop. of most public activities, given the physical half-life of 6.7 d, the
If infiltration occurs, clearance of the radiotracer from the site can be mean effective blood elimination half-life of 3.5 6 1.4 h, and the
facilitated with warm packs, compression, and elevation (13). Infil- mean terminal blood half-life of 71 6 28 h (6). Extra precautions
tration must be reported to radiation safety for monitoring and cal- should be taken to minimize exposure of young children and pregnant
culation of skin dose. women. The mathematics of release criteria for any nuclear medicine
therapy patients have been addressed comprehensively (14). The
RADIATION SAFETY
RADAR website has an online tool that allows for calculation of
cumulative doses to family members or members of the public from
Contamination exposure to patients treated with 177Lu-DOTATATE (16).
With a half-life of 6.6 d, 177Lu raises the possibility of pro-
longed contamination. Blood and urine are the main sources of Pregnancy
contamination during and after radionuclide administration. Be- Radiopharmaceutical therapy is almost universally contra-
cause 177Lu-DOTATATE is primarily excreted in urine, with a indicated during pregnancy. Therapy must be delayed until
cumulative excretion of 44% within 5 h, 58% within 24 h, and childbirth or termination of pregnancy. Breast feeding should be
65% within 48 h after administration, the main focus for individ- stopped for treatment and not be restarted until 2.5 mo after the final
ual patients for the first 3 d after therapy is on preventing urinary therapy. Future children may be breastfed. Contraception should
contamination (6). Of note, when produced by neutron activation, there be used for 6 mo after completion of the final treatment.
is a long-lived 177Lu contaminant, 177mLu, which has a half-life of Issues with Cremation and Patient Death
160 d and needs to be surveyed for before disposal of radioactive It is important to notify the local radiation safety officer of a
waste from the treatment center. This issue is of greater impor- death involving a radioactive patient. Deceased patients should
tance in locations that treat patients in an inpatient setting. Emesis be appropriately labeled, and the death certificate should note
can contain small amounts of radioactive material and should that the patient is radioactive. If possible the radiation safety officer
be treated as contaminated and disposed of appropriately. should appropriately train the medical examiners and the mortuary
personnel, as well as perform radiation surveys. Please refer to the
Preparation for Inpatient Therapy National Council on Radiation Protection and Measurements (NCRP)
For patients who require an overnight stay, typically due to Report no. 161 (NCRP 2008) for additional guidance on the manage-
medical complications, the recommendations largely follow those ment of radiation accident victims, regarding guidelines for the
already in place for 131I inpatients, noting that the external dose medical examiner and mortuary personnel (17).
rate from 177Lu is significantly lower than 131I given the lower
energy and abundance of its g-emissions. Nursing personnel will DOSIMETRY AND POSTTREATMENT IMAGING
need to be instructed in pertinent radiation safety precautions (i.e.,
potential for contamination related primarily to the patient’s blood Although dosimetry was not a part of the phase III NETTER-1
and urine), but also be advised that nausea and vomiting related to trial, there may be a role for patient-specific dosimetry when
the administration of the amino acid solution may occur. Universal considering cumulative renal and bone marrow dose. There is a large
precautions (e.g., gloves, gowns, shoe covers) should be used to variability in tumor and organ uptake of radiolabeled SSAs across
avoid contact with patient bodily fluids. If blood or urine speci- patients, which suggests that tailored dosimetry may be useful for
mens are needed for laboratory testing, nursing staff should be
advised to collect the smallest amount necessary for testing. Nurs- TABLE 4
ing staff should be provided with radiation monitoring devices Radiation Safety Recommendations After 177Lu-DOTATATE
(passive dosimeter, direct-reading dosimeter). Ideally, radiation Treatment
safety staff should help prepare the patient’s bed, floor, and bath-
room to minimize potential radioactive contamination from pa- Duration Recommendations
tient bodily fluids. Institutional radiation safety guidelines should
be developed for general nursing care of 177Lu-DOTATATE Sleep
inpatients including approaches to medical emergencies or patient 3d Sleep in separate bed, avoid intimate contact. For
deaths before a 177Lu-DOTATATE therapy program is established. infants/children or pregnant partner, the time
period should be extended.
Release Criteria Urination
To ensure that radiation dose to members of the public remains
3d Flush toilet twice with the lid closed after each use
less than 5 mSv (500 mrem), the patient should be provided with (all patients should be advised to sit down when
instructions (Table 4) at discharge. Each center should determine its urinating to minimize/avoid splashing), and to
own recommendations based on each patient’s specific circumstances use separate towels and washcloths.
and local regulations, but we have provided a basic guidance in
General recommendations
Table 4 for minimizing exposure to others and potential urine
contamination (14). The average exposure at 1 m immediately 3d Use a general distance guideline of no closer than
after treatment is 1.8 6 0.5 mrem/h and at the time of discharge 3 feet for not more than 1 h per day. Try to
maintain a distance of 6 feet from others.
is 0.9 6 0.4 mrem/h (combined institutional experiences from more
Minimize public transportation and use of public
than 100 therapies). This exposure is less than that from 131I therapy
facilities.
and below release criteria from published Nuclear Regulatory Com- Return to work in 3 d, depending on patient
mission guidelines (15). The time periods for following various tolerance.
instructions will vary, but 3 d should be sufficient for resumption

SOMATOSTATIN RECEPTOR–BASED PRRT WITH 177LU-DOTATATE • Hope et al. 941

 risk is myelodysplastic syndrome or acute leukemia, which occurs
in roughly 2%–3% of patients at a median of 2 y after therapy.
Although little can be done during treatment to minimize marrow
toxicity, there are possible risk factors for the development of
toxicity such as prior chemotherapy (6,23,24).

Renal Toxicity
Because of the high exposure to the kidneys from the renal
excretion of the radiotracer, renal toxicity is possible. With the
introduction of concurrent amino acids for renal protection and the
use 177Lu-labeled compounds in place of 90Y-labeled compounds,
the rates of renal toxicity are low, with long-term grade 3–4 renal
FIGURE 4. Whole-body images acquired after administration of 177Lu- toxicity less than 2% (4,23). Variations in individual kidney sen-
DOTATATE in different therapy cycles. sitivity to radiation may explain the variability seen between renal
dose and the subsequent development of renal toxicity. For example,
177Lu-DOTATATE
there is evidence that patients with long-standing diabetes or hyper-
therapy (18). For example, 1 study showed a
tension may be at higher risk for renal dysfunction after 177Lu-
biologically effective dose to the kidneys ranging from 9 to more
DOTATATE treatment (19). Nevertheless, severe renal toxicity is
than 40 Gy (19). Please see Supplemental Table 2 for standard-
rare (,5%) when using the current administration guidelines (4,19).
ized dose estimates for the reference adult for 177Lu-DOTATATE
(20). Although 68Ga-DOTATATE may be used for diagnostic eval-
uation of tracer uptake, it cannot be used for dosimetry planning FOLLOW-UP
due to its short (68 min) half-life. However, 177Lu g-rays are suit- Monitoring of patients after PRRT treatment is an essential part
able for g-camera imaging (Supplemental Table 3), and imaging for of the treatment plan. The recommended monitoring should include
dosimetry may be performed after the initial therapy cycle (Fig. 4). clinical evaluation to assess symptoms and detection of possible
Further details about potential imaging protocols for dosimetry treatment sequelae, laboratory, and imaging tests (Table 5).
can be found in the supplemental materials.
Clinical Evaluation
TOXICITY Clinical evaluation by the treating or primary team should ide-
ally be conducted at 1 mo, 3 mo, 6 mo, and 12 mo after PRRT.
Rates of toxicity vary between patients, and heavily pretreated If there are no laboratory abnormalities or clinical symptoms con-
patients have higher rates of PRRT-associated toxicity. In partic- cerning for posttreatment sequelae, patients can resume clinical
ular, liver toxicity has been reported in patients who have had follow-up per the primary team. National Comprehensive Cancer
extensive prior liver-directed therapy or who are treated with 90Y- Network (NCCN) guidelines recommend follow-up intervals of 3–
based PRRT (21). The following sections focus on bone marrow 12 mo based on clinical presentation (25). Clinical symptoms
and kidney toxicity in more detail. and presentations that could reflect possible progression, increased
symptoms from carcinoid syndrome, or posttreatment sequelae war-
Bone Marrow Toxicity
rant closer monitoring.
Grade 3 and 4 thrombocytopenia and neutropenia occur in #5%
of patients and resolve within 8 wk (4,22). Grade 3 and 4 lym- Laboratory Tests and Markers
phopenia is more common but is rarely of clinical significance Blood tests including complete blood count with differential,
since opportunistic infections are not observed in association with aspartate aminotransferase, alanine aminotransferase, alkaline phos-
177Lu-DOTATATE. The most significant long-term hematologic phatase, total bilirubin, albumin, and serum creatinine/GFR should

TABLE 5
Recommended Monitoring Interval After Completion of PRRT

Time after treatment* Clinical evaluation Laboratory tests† Markers‡ Diagnostic imaging
)
2–4 wk X X
2 mo X X¶
3 mo X X Per team
6 mo X X Per team X
12 mo X X Per team X
Long term Per team Per team Per team Per team

*Increase monitoring based on clinical presentation, symptoms, concern for progressive disease, or posttreatment sequelae.
†
Complete blood count with differential, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin,
albumin, and serum creatinine/GFR
‡
Monitoring of markers should be based on clinical indication/presentation.
¶
Imaging is recommended once between one and three months after therapy.

942 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 60 • No. 7 • July 2019

be monitored at roughly 1 mo, 3 mo, 6 mo, and 12 mo after treatment. 6. Lutathera [package insert]. New York, NY: Advanced Accelerator Applications;
If all blood tests are within normal limits, a complete blood count and 2018.
7. de Jong M, Krenning E. New advances in peptide receptor radionuclide therapy.
serum creatinine should be monitored at least yearly or sooner if J Nucl Med. 2002;43:617–620.
clinically indicated or per primary team. If there are any abnormal- 8. Bodei L, Mueller-Brand J, Baum RP, et al. The joint IAEA, EANM, and
ities in blood tests, more frequent monitoring is recommended. SNMMI practical guidance on peptide receptor radionuclide therapy
Both secondary myelodysplastic syndrome and acute leukemia (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013;40:
800–816.
are known toxicities of PRRT. Increased monitoring is recom-
9. Roscoe JA, Morrow GR, Aapro MS, Molassiotis A, Olver I. Anticipatory nausea
mended for those patients with persistent cytopenias with blood and vomiting. Support Care Cancer. 2011;19:1533–1538.
tests until recovery. In addition, hematology consult should be 10. Abbott A, Sakellis C, Andersen E. Nuts and bolts of 177Lu-DOTATATE admin-
considered for patients with persistent cytopenias. istration in the nuclear medicine division: guidance from a single institute’s
Patients with mild to moderate renal impairment after PRRT experience. J Nucl Med Technol. August 3, 2018 [Epub ahead of print].
11. de Keizer B, van Aken MO, Feelders RA, et al. Hormonal crises following re-
treatment warrant closer monitoring with serum creatinine mea- ceptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-
surements. In addition, nephrology consult should be considered DOTA0,Tyr3]octreotate. Eur J Nucl Med Mol Imaging. 2008;35:749–755.
for patients with persistent or worsening renal impairment. 12. Tapia Rico G, Li M, Pavlakis N, Cehic G, Price TJ. Prevention and management
There are no formal recommendations for following tumor of carcinoid crises in patients with high-risk neuroendocrine tumours undergoing
peptide receptor radionuclide therapy (PRRT): literature review and case series
markers after PRRT. NCCN NET guidelines recommend follow- from two Australian tertiary medical institutions. Cancer Treat Rev. 2018;66:
ing markers if clinically applicable every 3–12 mo (25). 1–6.
13. Bonta DV, Halkar RK, Alazraki N. Extravasation of a therapeutic dose of 131I-
Diagnostic Imaging Evaluation metaiodobenzylguanidine: prevention, dosimetry, and mitigation. J Nucl Med.
In most cases, diagnostic imaging should be done at 1–3 mo, 6 2011;52:1418–1422.
mo, and 12 mo after the completion of all treatment cycles. There- 14. Siegel JA, Marcus CS, Stabin MG. Licensee over-reliance on conservatisms in
NRC guidance regarding the release of patients treated with 131I. Health Phys.
after, patients should undergo diagnostic imaging based on treat-
2007;93:667–677.
ment response. It is important to remain consistent with imaging 15. Regulatory Guide 8.39: Release of Patients Administered Radioactive Materials.
modalities. NCCN guidelines recommend following patients with U.S. Nuclear Regulatory Commission website. https://www.nrc.gov/docs/ML0833/
contrast-enhanced abdominal and pelvic CT or MRI with contrast ML083300045.pdf. Accessed February 21, 2019.
along with chest CT with or without contrast (if clinically in- 16. Stabin MG. RADAR patient exposure radiation dose calculator. RADAR web-
site. http://www.doseinfo-radar.com/ExposureCalculator.html. Accessed Febru-
dicated) every 3–12 mo (25). MRI of the liver with gadoxetate ary 21, 2019.
disodium (Eovist) should be considered for those patients with 17. National Council on Radiation Protection and Measurements. Management of
liver-dominant disease (26,27). Increased monitoring is recom- Persons Contaminated with Radionuclides. Bethesda, MD: National Council on
mended for clinical presentation concerning for possible progres- Radiation; 2008.
18. Cremonesi M, Botta F, Di Dia A, et al. Dosimetry for treatment with radio-
sive disease, clinical worsening, or possible posttreatment sequel.
labelled somatostatin analogues: a review. Q J Nucl Med Mol Imaging. 2010;54:
If there is evidence of progression or equivocal findings on CT or 37–51.
MRI, SSTR-based imaging with 68Ga-DOTATATE PET should 19. Bodei L, Cremonesi M, Grana CM, et al. Peptide receptor radionuclide therapy
be considered and is preferred over SSTR scintigraphy (111In- with 177Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging.
pentetreotide) (2). 2011;38:2125–2135.
20. Sandström M, Garske-Román U, Granberg D, et al. Individualized dosimetry of
It should be noted that the first imaging study performed after kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treat-
the completion of PRRT can be complicated by pseudoprog- ment. J Nucl Med. 2013;54:33–41.
ression (28). In nearly 10% of patients with stable disease, met- 21. Riff BP, Yang Y-X, Soulen MC, et al. Peptide receptor radionuclide therapy-
astatic disease can increase in volume transiently, presumably due induced hepatotoxicity in patients with metastatic neuroendocrine tumors. Clin
Nucl Med. 2015;40:845–850.
to edema from radiation to the tumor. Diagnostic imaging during
22. Brabander T, van der Zwan WA, Teunissen JJM, et al. Long-term efficacy,
the course of PRRT can be considered in patients with relatively survival, and safety of [177Lu-DOTA(0),Tyr(3)]octreotate in patients with gastro-
aggressive tumors, or patients with clinical evidence of progression. enteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017;23:
4617–4624.
23. Bodei L, Kidd M, Paganelli G, et al. Long-term tolerability of PRRT in 807
CONCLUSION patients with neuroendocrine tumours: the value and limitations of clinical fac-
177Lu-DOTATATE is an effective treatment for patients with tors. Eur J Nucl Med Mol Imaging. 2015;42:5–19.
24. Bergsma H, van Lom K, Raaijmakers MHGP, et al. Persistent hematologic
NETs. The above guidelines provide information on how to safely dysfunction after peptide receptor radionuclide therapy with 177Lu-DOTATATE:
administer this novel treatment to patients. incidence, course, and predicting factors in patients with gastroenteropancreatic
neuroendocrine tumors. J Nucl Med. 2018;59:452–458.
25. Kulke MH, Shah MH, Benson AB, et al. Neuroendocrine tumors, version 1.2015.
REFERENCES
J Natl Compr Canc Netw. 2015;13:78–108.
1. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med. 1999;340:858–868. 26. Tirumani SH, Jagannathan JP, Braschi-Amirfarzan M, et al. Value of hepatocel-
2. Hope TA, Bergsland EK, Bozkurt MF, et al. Appropriate use criteria for so- lular phase imaging after intravenous gadoxetate disodium for assessing hepatic
matostatin receptor PET imaging in neuroendocrine tumors. J Nucl Med. 2018;59: metastases from gastroenteropancreatic neuroendocrine tumors: comparison with
66–74. other MRI pulse sequences and with extracellular agent. Abdom Radiol. 2018;43:
3. Kwekkeboom DJ, Kam BL, van Essen M, et al. Somatostatin-receptor-based 2329–2339.
imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr 27. Morse B, Jeong D, Thomas K, Diallo D, Strosberg JR. Magnetic resonance
Relat Cancer. 2010;17:R53–R73. imaging of neuroendocrine tumor hepatic metastases: does hepatobiliary phase
4. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-Dotatate for imaging improve lesion conspicuity and interobserver agreement of lesion mea-
midgut neuroendocrine tumors. N Engl J Med. 2017;376:125–135. surements? Pancreas. 2017;46:1219–1224.
5. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiola- 28. Brabander T, van der Zwan WA, Teunissen JJM, et al. Pitfalls in the response
beled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, evaluation after peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]
and survival. J Clin Oncol. 2008;26:2124–2130. octreotate. Endocr Relat Cancer.2017;24:243–251.

SOMATOSTATIN RECEPTOR–BASED PRRT WITH 177LU-DOTATATE • Hope et al. 943