Iodine-131labeled Meta-Iodobenzylguanidine

Therapy of Children with Neuroblastoma:

Program Planning and Initial Experience
Suzanne Shusterman, MD,*, Frederick D. Grant, MD,, William Lorenzen, MS,
Royal T. Davis, CNMT, RT(N), Stephen Laffin, CNMT, RT(N,) Laura A. Drubach, MD,,
Frederic H. Fahey, DSc,, and S. Ted Treves, MD,
Patients with high-risk neuroblastoma have a poor prognosis, especially in cases of
recurrent or relapsed disease. Iodine-131labeled meta-iodobenzylguanidine (131I-MIBG)
can be an effective and relatively well-tolerated agent for the treatment of refractory
neuroblastoma. Establishing an MIBG therapy program requires a great deal of planning,
availability of hospital resources, and the commitment of individuals with training and
expertise in multiple disciplines. Providing 131I-MIBG therapy requires physical facilities
and procedures that permit patient care in compliance with the standards for occupational
and community exposure to radiation. Establishment of a successful 131I-MIBG therapy
program also requires a detailed operational plan and appropriate education for caregivers,
parents, and patients.
Semin Nucl Med 41:354-363 2011 Elsevier Inc. All rights reserved.

he prognosis for children with neuroblastoma varies

widely and depends on both clinical features, including
patient age at diagnosis and tumor stage, and tumor biology,
such as amplification of the MYCN oncogene (myc myelocytomatosis viral related oncogene, neuroblastoma derived).1
Patients with localized disease and favorable tumor biology
almost always are cured with surgery alone, and those with
locally aggressive tumors with favorable biology usually are
treated successfully with a combination of surgical resection
and moderately intensive chemotherapy. However, more
than one-half of patients present with metastatic disease
and/or adverse tumor-specific biological features. These children with high-risk disease are treated with aggressive multimodal therapy, including chemotherapy, surgical resection,
local radiation therapy, consolidation with high-dose chemo-

*Department of Pediatric Oncology, Dana-Farber Cancer Center, Boston,

MA.
Division of Hematology/Oncology, Department of Medicine, Childrens
Hospital Boston, Boston, MA.
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Childrens Hospital Boston, Boston, MA.
Joint Program in Nuclear Medicine, Harvard Medical School, Boston, MA.
S. Shusterman and F.D. Grant contributed equivalently to this work.
Address reprint requests to S. Ted Treves, MD, Division of Nuclear Medicine
and Molecular Imaging, Childrens Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. E-mail: treves@childrens.harvard.edu

354

0001-2998/11/$-see front matter 2011 Elsevier Inc. All rights reserved.

doi:10.1053/j.semnuclmed.2011.06.001

therapy with autologous hematopoietic stem cell rescue, and

minimal residual disease therapy that includes tumor-directed monoclonal antibody therapy and the differentiating
agent 13-cis-retinoic acid.2,3 Despite such intense therapy,
cure rates remain 50%, and neuroblastoma accounts for
15% of all deaths in pediatric oncology patients. Although
most patients with high-risk neuroblastoma respond to
front-line therapy, the disease often relapses, and the prognosis for children with recurrent or refractory neuroblastoma
is dismal, with most dying from progressive disease. There
currently is no accepted successful treatment regimen for
neuroblastoma patients with refractory disease, and most of
these children suffer from significant tumor-related pain at
the end of life that is often difficult to treat.
Iodine-131-labeled meta-iodobenzylguanidine (131I-MIBG)
was developed first as an imaging agent for the detection and
localization of pheochromocytoma.4 Soon after, Kimmig et
al5 demonstrated its utility for imaging neuroblastoma.6 Approximately 90% of neuroblastoma tumors concentrate
MIBG, with uptake in both primary tumors and metastatic
sites.7 This high MIBG avidity and the known radiosensitivity
of neuroblastoma makes 131I-MIBG a potential therapeutic, as
well as imaging, agent. Because of the poor prognosis of
high-risk neuroblastoma patients, 131I-MIBG has been studied as a targeted therapy for both relapsed and newly diagnosed neuroblastoma. It has been used as both as a single

131I-MIBG

therapy of neuroblastoma

agent and in combination with other drugs with proven activity in neuroblastoma.
Establishing and operating an MIBG therapy program requires a great deal of planning and commitment of hospital
resources. Physical facilities must be available to administer
131I-MIBG safely and in regulatory compliance with the standards for occupational and community exposure to radiation. An effective operational and procedural plan is necessary to initiate and maintain an MIBG therapy program.
Ongoing education is needed for caregivers, families, and
patients. The participation and commitment of individuals
with training and expertise in multiple disciplines, including
oncology, nuclear medicine, medical physics, radiopharmacy, nursing, radiation safety, child-life, and hospital engineering and facilities management, are necessary to successfully implement and operate a program. This review will
summarize the clinical development of 131I-MIBG for the
treatment of neuroblastoma and describe our single-institution experience in establishing a therapeutic MIBG program
for neuroblastoma patients.

Clinical Development
of 131I-MIBG Therapy
Development of
131I-MIBG as a Single Agent
There has been extensive testing of 131I-MIBG as a therapeutic
agent in patients with refractory neuroblastoma. Early clinical series and case studies demonstrated effective disease palliation, but, because of small numbers, no definite correlation
could be established between dose and response or toxicity.8-14 Myelosuppression was the most common toxicity
reported, and nonhematologic toxicity was generally mild.
The authors of 2 formal Phase 1 studies have more clearly
delineated dosing and toxicity of 131I-MIBG and have clearly
suggested clinical activity. The U.K. Childrens Cancer Study
Group ran a multicenter Phase 1 study of 131I-MIBG in 25
relapsed or refractory neuroblastoma patients.15 Dosimetry
was performed on all patients at study entry, and then 131IMIBG dosing was calculated so that patients received wholebody radiation doses of 1.0 Gy (n 2), 2.0 Gy (n 13), and
2.5 Gy (n 10). Nausea and vomiting as well as asymptomatic transient changes in blood pressure were seen temporally
related to the MIBG infusion. The major toxicity was bone
marrow suppression, particularly thrombocytopenia, which
clearly was correlated with dose. No patients developed febrile neutropenia. Of 24 patients assessed for response to
treatment, 8 (33%) had a partial response to treatment, and 9
(38%) had stable disease. There was no correlation between
prescribed activity or whole-body radiation dose and response.
The other Phase 1 trial was performed by the Childrens
Cancer Group, which treated 30 refractory neuroblastoma
patients with escalating doses of 3-18 mCi/kg of 131I-MIBG.16
For comparison with the U.K. study, the mean whole-body
radiation dose was estimated to be 1.52 Gy at 9 mCi/kg, 2.28
Gy at 12 mCi/kg, 3.51 Gy at 15 mCi/kg, and 3.29 Gy at 18

355
mCi/kg. Nonhematologic toxicity was relatively mild, consisting of nausea and vomiting on the first 2 days of treatment
(easily controlled with antiemetics), grade 2 infusional hypertension in 2 patients, and asymptomatic hypothyroidism
diagnosed in patients 4-8 weeks after treatment. Similar to
what was seen in the U.K. study, hematologic toxicity was
significant, particularly thrombocytopenia, and was clearly
correlated with dose. Sixty-two percent of patients had grade
4 thrombocytopenia, and 46% of patients had grade 4 neutropenia. Only 3 patients had episodes of fever and neutropenia after treatment, and only 1 had a proven infection. No
patients treated with 12 mCi/kg or less required an autologous stem cell rescue for prolonged neutropenia (defined in
the protocol as an absolute neutrophil count (ANC)
200/L for more than 2 weeks) whereas 2 patients treated
with 15 mCi/kg (n 5) and 4 patients treated with 18
mCi/kg required stem cell rescues. There was one complete
response and 10 partial responses for an overall response rate
of 37%. Ten of the responses were seen in patients treated
with 12 mCi of 131I-MIBG or more. Six patients had disease
stabilization for 3-37 months with a median of 8 months. The
study demonstrated a maximal tolerated dose (MTD) of 131IMIBG of 12 mCi/kg without stem cell support and 18 mCi/kg
with stem cell support, establishing the feasibility of dose
intensification with available stem cell support.
Using the MTD established in the Childrens Cancer
Group study, a Phase 2 study of 164 patients with refractory
or relapsed neuroblastoma was performed at 3 institutions in
the United States.17 Patients were treated with 131I-MIBG at
doses of either 12 mCi/kg or 18 mCi/kg depending on stem
cell availability. As seen in the Phase 1 studies, the major
toxicity was hematologic: 88% of patients required platelet
transfusion, 65% of patients had an ANC nadir 500 L,
and 21% of patients had an infectious event. Approximately
one-third of patients treated at a dose of 18 mCi/kg required
a hematopoietic stem cell rescue on the basis of either an
absolute neutrophil count 200/L for more than 2 weeks
despite growth factor support or prolonged platelet transfusion dependence. The objective response rate was 25% for
the 16 patients treated with12 mCi/kg and 37% for the 147
patients treated with 18 mCi/kg. An additional 39% of patients had disease stabilization. Factors predictive of response
included age 12 years, less than 3 previous treatment regimens, longer time from diagnosis to 131I-MIBG therapy, and
disease isolated to either soft tissue or bone/bone marrow
alone (as compared with patients with both soft-tissue and
bone/bone marrow disease).
Further dose intensification was investigated in a New Approaches to Neuroblastoma Therapy (NANT) Phase 1
study,18 in which 131I-MIBG was given in 2 closely spaced
infusions (14 days apart) followed by stem cell rescue, with
dose adjusted to reach a target cumulative red marrow index.
Twenty-one patients were treated at 4 dose levels with cumulative dosing of 131I-MIBG ranging between 22 and 51 mCi/
kg. No patient had a dose-limiting toxicity, but 6 of 8 patients
treated at the highest dose level had reversible grade 3 nonhematologic toxicity, suggesting a cumulative MTD of 36
mCi/kg. The hematologic toxicity was abrogated by the re-

S. Shusterman et al

356
quired stem cell rescue at day 28, demonstrating that 131IMIBG can be safely dose escalated with stem cell support.
Seven patients never had an ANC 500/L, and 2 patients
did not require platelet transfusions. The median time to
neutrophil engraftment was 13 days. Although 8 of 21 patients had a partial response by semiquantitative MIBG score,
the objective response rate was only 10%, largely because of
persistence or progression of bone marrow disease. There
was a decrease in the expected red marrow dose for the second infusion compared to the first in 13 of 20 patients, which
could be explained by either a lower tumor burden at the
time of second infusion or persistent saturation of the norepinephrine transporter.
A recent study from the Childrens Hospital of Philadelphia also investigated the safety and efficacy of tandem 131IMIBG infusions.19 Patients with tumor response or stable
disease after receiving 18 mCi/kg 131I-MIBG were treated
with a second dose 42-100 days later. Patients who had low
blood counts before the second infusion were given a stem
cell rescue 2 weeks after the second infusion. Of 76 patients
treated with the first dose of 131I- MIBG, 30% of had an
objective response, and 49% showed stable disease. Fortyone patients received a second dose of 131I-MIBG with a response rate of 29% with an additional 37% showing stable
disease. The toxicity was mainly hematologic and consistent
with what was seen in previous studies. After the second
MIBG infusion, 71% of patients became platelet-transfusion
independent, including 16 of the 24 patients who were transfusion dependent at the time of the second infusion. Most of
the patients who remained transfusion dependent had progressive bone marrow involvement. This study further supports the safety and suggests efficacy of dose intensification of
I-MIBG in refractory neuroblastoma.
131I-MIBG

in Combination Therapies

In addition to use as a single agent, 131I-MIBG also has been

evaluated in combination with other agents that have known
activity in neuroblastoma and are potential radiosensitizers.
One group has reported experience in combining cisplatin
with 131I-MIBG.20,21 Patients were treated with cisplatin (50
mg/m2) on days 0 and 7 and MIBG (100-130 mCi) on days 1
and 8. The main toxicity was myelosuppression. In 1 series of
4 patients, 3 with relapsed, progressive stage IV neuroblastoma and 1 with newly diagnosed stage IV neuroblastoma, 2
complete responses and 1 partial response was observed. A
report from the same group of 16 patients treated with a
combination of cisplatin and 131I-MIBG as well as other chemotherapy also showed promising results.22
Another highly active agent in neuroblastoma that has
been combined with 131I-MIBG is topotecan. In a feasibility
study from the United Kingdom, 8 patients were treated with
12 mCi/kg 131I-MIBG on days 1 and 15 to give a total wholebody radiation dose of 4 Gy followed by topotecan 0.7 mg
m2 on days 1 through 5 and 15 through 19. All patients
received a stem cell rescue on day 27. This combination was
well-tolerated without significant hematologic toxicity or un-

expected side effects.23 Response rates were not reported in

this pilot study.
The NANT Consortium just completed a Phase 1 study in
which they combined 131I-MIBG with irinotecan, another
agent that is active in relapsed neuroblastoma and a known
radiation sensitizer. Another current NANT consortium
study combines 131I-MIBG with vorinostat, a histone deacetylase inhibitor that has been shown to increase the expression
of functional norepinephrine transporters.24
Given the proven efficacy of myeloablative therapy in
newly diagnosed high-risk neuroblastoma patients,2 131IMIBG also has been explored as a component of myeloablative regimens in several pilot studies. In a German study, 11
patients were treated with 131I-MIBG 0.58 GBq kg1 followed
by myeloablative doses of carboplatin, etoposide, and melphalan, followed by stem cell rescue.25 The most common
nonhematologic toxicities were fever and neutropenia, mucositis, diarrhea, and renal dysfunction, which were most
likely related to the chemotherapy. Patients engrafted relatively quickly with a mean time to reach an absolute neutrophil count 500/L of 11.6 days. Three patients went from
a partial response before pilot therapy to a complete response
at the end of treatment, and 1 patient went from no response
to a partial response after therapy.
In a similar pilot study at the University of Michigan, 12
patients were treated with a fixed dose of 131I- MIBG, 12 mCi
kg1, on day 21 followed by myeloablative carboplatin,
etoposide and melphalan on days 7 to 4, with autologous
marrow or stem cell rescue on day 0.26 Similar to the German
study, the most common nonhematologic toxicities were
mucositis, fever and neutropenia. Eleven of 12 patients engrafted within 15 days of stem cell rescue. Three of 8 patients
with metastatic disease and 3 of 4 patients with persistent
localized disease had a complete response to therapy.
The NANT consortium did a Phase 1 dose-escalation study
to define the maximal tolerated dose of 131I-MIBG followed
by fixed doses of myeloablative carboplatin, etoposide, and
melphalan with stem cell rescue.27 Twenty-two patients with
primary refractory neuroblastoma were treated in 2 cohorts,
depending on the patients glomerular filtration rate (GFR).
The MTD of 131I-MIBG for both the normal and low GFR
cohorts was 12 mCi/kg. The chemotherapy for the patients in
the low GFR cohort was reduced and dosed based on renal
function. Toxicity was comparable with what generally is
seen with myeloablative regimens, although there was a
greater-than-expected incidence of hepatic toxicity in the low
GFR cohort; 3 of 6 patients developed veno-occlusive disease. The overall response rate in this study was 27% with a
median event-free survival of 18 months and median overall
survival of 48.1 months. On the basis of these promising
results in refractory patients, the NANT consortium has recently completed a Phase 2 study at the MTD in refractory
neuroblastoma patients. In addition, the Childrens Oncology group is planning a pilot of 131I-MIBG with myeloablative
chemotherapy in newly diagnosed high-risk patients that
should open shortly.
In summary, 131I-MIBG is clearly active against refractory
neuroblastoma. Phase 1 and 2 studies show an objective re-

131I-MIBG

therapy of neuroblastoma

357

sponse in at least one-third of patients and disease stabilization in another 30%-40% of patients, which is superior to
almost every other novel agent studied in the setting of relapsed high-risk disease. Treatment-related nonhematologic
toxicity, even at substantial doses, is usually minimal and
hematologic toxicity can be abrogated with stem cell rescue.
Because of its high activity level and acceptable toxicity profile, 131I-MIBG is now being developed as part of initial therapy for newly diagnosed high-risk neuroblastoma patients by
the Childrens Oncology Group and others.

Table 1 Selection Criteria for a Treatment Room for Pediatric

131I MIBG Therapy

Establishing an
MIBG Therapy Program

131I

Initial Planning

Treatment Room Location

The first consideration regarding the establishment of an MIBG

therapy program is to determine the clinical demand and institutional resources available for this therapeutic approach. Although there is no specific threshold for determining clinical
need, the clinical demand must balance the substantial commitment of hospital resources and multidisciplinary effort needed
for this program. One factor may be the proximity and availability of other MIBG therapy programs. Developing formal business and clinical management plans can be an appropriate
part of the process of determining the need and feasibility of
an MIBG therapy program. At our institution, we estimated
that, of patients treated by our pediatric oncology program,
approximately 10-12 per year would be eligible for active or
anticipated 131I-MIBG clinical trials. In addition, our plan
anticipated 3-5 additional patients would be referred specifically for 131I-MIBG therapy.
A successful MIBG therapy program requires the commitment and active involvement of individuals from many fields
in both the planning and implementation of the program.
The clinical need for a therapy program must be driven by
pediatric oncologists that treat patients with neuroblastoma
and who will identify patients eligible for 131I-MIBG therapy.
One or more oncologists will need to take responsibility for
the medical care of patients during and after the therapy.
Nuclear medicine staff, including physicians, medical physicists, and nuclear medicine technologists, are necessary for
the planning and implementation of a therapy program, and
usually will oversee the handling, testing, and patient administration of the 131I-MIBG. Depending on the commercial
pharmacy supplying the 131I-MIBG, it will be helpful to have
a radiopharmacist involved in planning the receipt, preparation, and testing of the radiopharmaceutical. Nursing staff are
essential members of the planning and operations team, as
together with family members, nursing staff will provide
most direct patient care. Nursing managers likely will be
responsible for scheduling and planning the patients inpatient admission, and may take a lead in planning the logistical
aspects of a therapy program. The institutional Radiation
Safety officer must be involved in planning. Hospital engineers and facility managers have an important role, particularly in planning and directing any necessary facility renovations or new construction.

The choice of room to use as an 131I-MIBG treatment room is

based on both clinical and radiation safety criteria (Table 1).
In nearly all cases, a patient will be treated as an inpatient. It
is ideal to have the room in a patient care area with staff who
are familiar with caring for pediatric oncology patients to
increase patient comfort as much as possible during the period of radiation isolation. The room in which the patient will
stay after administration of therapy should be located and
designed to minimize the radiation exposure of caregivers
and other individuals. A private room is necessary and, because urine and other body secretions will be radioactive, the
bathroom cannot be shared with other patients. Because of
the gamma rays emitted from the 131I within the patient,
individuals near the patient also may be exposed to radiation.
For these reasons, the patients room and adjacent areas need
to be controlled with respect to radiation safety. The fundamental tenets of radiation safety of using time, distance, and
shielding to keep radiation exposure as low as reasonably
achievable (ie, ALARA) must be considered.
To limit exposure time, health professionals and family
members should plan to stay in the patient room for only
short periods. If the patients primary care will be provided
by a parent or other family member, it is useful to have an
area in which the caregiver can stay close to, but separated
from, the patient. Ideally, this is located adjacent or very close
to the patient room but is shielded from radiation exposure
from the patient. The parents should be able to observe their
child through either a window (of leaded glass if necessary)
or a video monitoring system. The nursing and medical staff
also should be able to view the patient by using a video
system. Radiation exposure in adjacent areas needs to be
controlled either through limiting access to these areas or the
use of radiation shielding.

Clinical Criteria
Oncological Nursing and clinical support
Clinical apparatus
Child life/engagement apparatus
Radiation safety criteria
Dedicated bathroom and sink
Limited patient and personnel occupancy in neighboring
areas
Corner or isolated room
Nearby area for caregivers
MIBG, iodine-131labeled meta-iodobenzylguanidine.

Room Design and Shielding

The patient treatment room likely will need additional radiation shielding. Although it may be possible to use a room
without additional shielding, this likely would require vacating adjacent patient rooms and the extensive use of portable
shields. Selecting a room with exterior walls or that is adjacent to areas that are not routinely inhabited can be helpful.
For example, if the room is several stories above the ground

S. Shusterman et al

358

Figure 1 Treatment room design. The I-131 MIBG treatment room that was designed for Childrens Hospital Boston.
There is an anteroom between the treatment room and hallway. The treatment room is located between another patient
room (PATIENT ROOM 2) and a stairwell. On the floor above was a general space and below was a two-story high
mechanical space. Shielding calculations were determined by the patient being located at point P, 1.2 m from the wall.
On the basis of our calculations, the wall between the treatment room and the adjacent patient room (A) required 2.5
of lead, the wall adjacent to the stairwell (B) required 0.65 cm of lead, the wall between the treatment room and the
anteroom (C) and the ceiling required 1.3 cm of lead, and the floor required 0.32 cm of lead. Walls D and E did not
require additional shielding as adequate protection was afforded by the primary barriers and distance.

and is at the corner of the building, the 2 exterior walls may

require no or very little additional shielding. However, in
most cases, the ceiling and several of the walls of the selected
room will require addition shielding. Determining the
amount of shielding necessary in each barrier requires
knowledge of the physical layout of the room and adjacent
areas and the radiation level to which the adjacent space
should be controlled. Assumptions must be made regarding
where within the room the patient will be located most of the
time, the maximum amount of radioactivity that a patient
may receive during a single therapy, and the likely duration
of stay. Assumptions also are made regarding the occupancy
of adjacent areas.
The occupancy for general areas, such as stairwells and
hallways, should be 0.0625. Working areas in which health
professionals and/or support staff are always present, such as
an office, are considered to have an occupancy factor of 1.00
for 40 hours per week. We assumed that the occupancy of
neighboring patient rooms is 0.25. Although the treatment
patient will be in this room for 24 hours a day, our assumption considers that no patient will occupy the neighboring
room for more than 3 months in a year. In general, external
walls above the first floor will not require additional shielding. In our design, the one external wall located 6 floors
above ground level did not require shielding.
The dose rate (DR) at a particular distance from the patient
is given by the following equation:

DR * A d2
Where DR is the dose rate in mSv/h, is the gamma
exposure constant for 131I (7.64 105 mSv MBq per m2 h),
A is the activity in MBq, and d is the distance from the location to the patient in m. Knowing A and d, one can use this
formula to calculate DR. Multiplying DR by the number of
hours of exposure yields the cumulative dose. In our case, we
calculated the cumulative dose for day 1 on the basis of 1000
mCi (37 GBq) and the cumulative dose for days 2-4 based on
500 mCi (18.5 GBq).
In our planning at Childrens Hospital Boston, we controlled the adjacent space such that no member of the public
would receive more than 100 mrem (1 mSv) in 1 year or 2
mrem (20 Sv) per week. We assumed that the patient would
spend the vast majority of time in bed and that the patient is
a point source located 30 cm from the wall at the head of the
bed. We also assumed that the maximum administered activity would be 1000 mCi (37 GBq) and that the maximum
stay would be 4 days. We also assumed that 50% of the
activity would be biologically eliminated in the first 24 hours,
so our calculations are determined by the full dose (1000
mCi, 37 GBq) on day 1 and half-dose (500 mCi, 18.5 GBq)
on days 2-4. In our case, 100 mrem (1 mSv) per year was
more limiting than 2 mrem (20 Sv) per week.
The floor plan of our treatment room and adjacent space is
shown in Fig. 1. We calculated the cumulative dose for the

131I-MIBG

therapy of neuroblastoma

4-day stay at a location 30 cm on the other side of each

barrier, multiplied it by appropriate occupancy factor for that
area and determined the cumulative dose for that location.
We then determined the amount of lead equivalent that
would be necessary to reduce this dose to 2 mrem (20 Sv)
over the 4 days by using the following formula:
Pb HVL ln 2 * ln CD 20
Where Pb is the amount lead equivalent (cm) necessary to
reduce the cumulative dose to 20 Sv, HVL is the half value
layer for lead (cm), and CD is the unshielded cumulative dose
(Sv). The cement in the floor and ceiling provides some
shielding. Based on the HVLs of each, 10 cm of concrete is
equivalent to about 0.6 cm of lead.
On the basis of these calculations, we determined that we
needed the following additional lead shielding: Wall A to the
neighboring patient room required 2.5 cm of lead, Wall B
required 0.65 cm of lead, Wall C and the ceiling required 1.3
cm of lead, and the floor required 0.32 cm of lead. The floor
and the ceiling had 10 cm of light-weight concrete, the equivalence of 0.6 cm of lead which was considered in their shielding design.

Operational Planning
A multidisciplinary group is needed for planning the operations and procedures of a MIBG therapy program. Ideally,
there is an individual contact for each of the involved departments and disciplines. The choice of radiopharmacy supplying the 131I-MIBG may be determined by availability, research
support, and regulatory constraints. The nuclear medicine
department may be best able to negotiate product availability, supply schedule, and shipping details with the commercial radiopharmacy.
As 131I-MIBG for therapy remains an experimental agent and
involves human administration of large doses of radioactivity,
appropriate regulatory approval is needed. Typically, an oncologist will be the principal investigator on the research protocols
necessary to administer 131I-MIBG, but in some circumstances it
could be appropriate that a nuclear medicine physician has this
role. Approval by internal committees, including the Institutional Review Board for human subjects and the Radiation Safety
Committee, should be obtained before a program is made operational. These committees should provide oversight of clinical
trial design, investigator authorization for administration of the
radiopharmaceutical, details of therapy room design, establishment of radiation safety plans, creation of the educational
and training programs, and any other additional radiation or
patient safety issues related to the proposed therapy program.
The Radiation Safety officer, supported by the Radiation
Safety Committee, is the most appropriate institutional liaison with federal or state radiation regulatory authorities, including either the U.S. Nuclear Regulatory Commission or
state authorities, if the institution is located in an agreement
state. Most institutions will need to submit a radioactive license amendment to the appropriate licensing agency to increase the maximum possessed activity of radioactive material, specifically 131I. On the basis of our anticipated use, it

359
was determined that we would increase our 131I possession
limit to 111 GBq. For family caregivers, we requested a 2 rem
(20 mSv) dose limit, rather than the 100 mrem (1 mSv) dose
limit that would apply to them as members of the public. As
part of the approval process, we agreed that family caregivers
would receive radiation safety training and be provided specific information regarding how to keep their exposures
ALARA28 during the course of the therapy, that caregivers
would be monitored for radiation exposure using real-time
radiation dosimeters, and that the discharge of patients/subjects would be based on established regulatory release criteria
and include written instructions and information on how to
maintain exposures ALARA after discharge.
Many states have requirements that the construction/renovation of hospital facilities be approved by governmental
agencies. This typically is coordinated through the existing
construction management and planning groups of the institution. A small working group, including representatives
from oncology, nuclear medicine, nursing, and appropriate
departments in hospital administration, may be helpful to
plan the insurance approvals and other logistical steps that
will be needed before each admission. Approval by all appropriate internal committees and regulatory agencies took approximately 16 months.

Training and Education

Training and education was a very important component of
the successful implementation of our 131I-MIBG therapy program. This included developing and refining medical and
nursing guidelines for patients receiving treatment, developing educational tools for patients and parents, and developing educational tools for staff caring for the patients. Most
caregivers, including oncologists and nursing staff, had no
experience caring for patients after therapeutic administration of a radiopharmaceutical. Radiation safety staff, assisted
by nuclear medicine, took the lead in radiation safety training. However, no one, including nuclear medicine staff, had
prior experience with administration of the large radiopharmaceutical doses used for 131I-MIBG therapy. Therefore, radiation safety, nuclear medicine, and nursing staff visited
other institutions with active 131I-MIBG therapy programs
and collaborated in education and planning for our program.
Patient care staff, including nurses, that are assigned to the
inpatient unit annually complete an online radiation safety
class that is designed specifically to address the safety issues
associated with 131I-MIBG therapy. This is augmented by
one-on-one training as needed.

Treating Patients with

131I-MIBG

Family Education
After administration of 131I-MIBG therapy, much of the direct
care of the patient is provided by one or more family members. We typically request that, when possible, 2 parents or
other family care givers be involved in caring for the patient
during the hospital stay. Radiation safety and nursing staff
help orient patients and families to the therapy process before

S. Shusterman et al

360
admission. Those who will be involved in patient care receive
extensive training as part of this orientation process. We have
found it useful to provide PowerPoint presentations for selfdirected learning that is then reinforced during meetings
with nursing and radiation safety staff at the time of admission. Family caregivers receive training in basic patient care,
appropriate use of personal protective clothing, handling and
disposal of body fluids, and child-life issues. Radiation safety
topics include the concepts of time/distance/shielding and
the difference between radiation exposure and radiation contamination. Training covers the use of shielding, management of possible spills or contamination, using a dosimeter,
and personal surveys. At the completion of training, family
caregivers sign a caregiver contract that outlines all the requirements and responsibilities that are expected of the caregivers. This document serves to specify and solidify the relationships and expectation between caregivers, healthcare
providers, and radiation safety.

Clinical Care
In our institution, we have established an ongoing working
group to facilitate the planning of each admission as well as to
implement improvements in the overall process of providing
131I-MIBG therapy. Clinical care is provided by oncology
nursing and physician staff. Because 131I-MIBG may have
cardiovascular effects due to alteration in sympathetic activity, patients are monitored with a cardiac monitor and automated blood pressure cuff during the 131I-MIBG infusion.
After completion of the radiopharmaceutical infusion, older
patients are encouraged to void frequently to minimize the
dwelling time of excreted activity in the bladder. In younger
patients, an indwelling uretheral catheter is placed and maintained until the patient is discharged from the hospital. The
catheter drains into a closed collection system that is placed
in a lead container. The collected urine is then drained into
the toilet by trained staff or family members.
Only medically stable patients are selected for 131I MIBG
therapy. This decreases the likelihood of acute decompensation requiring intensive medical interventions for a patient
that has received the radiopharmaceutical. However, on-call
staff physicians and house officers must be including in training. Key staff members from the intensive care units also have
been included in planning and training. Fortunately, to date,
no patient has experienced a medical incident requiring
transfer to another medical or intensive care unit or intervention by critical care specialists.
All individuals wear personal protective equipment, including hospital gowns, booties, and gloves. The use of personal protective equipment helps prevent personal contamination to reduce direct radiation exposure and to prevent
tracking of contamination to locations outside the patients
room. Staff and caregivers receive specific training on the
donning and doffing of this personal protective equipment.
Personal radiation protective equipment, such as a lead
apron, will not be effective and is not appropriate for either
staff or family caregivers.
Because these patients are typically young children and

need to stay in the hospital for several days, it is very helpful

to have an experienced child life specialist involved in the
patients care. Such a program may be easier to coordinate if
child life specialists are available on the unit where the patient is staying. They can work with the patient, family members, and nursing staff to plan age-appropriate distraction
activities. Older patients will want electronic games, movies,
and cell phones to communicate with friends and family,
whereas younger children may be comforted by a security
object, such as a stuffed animal. Care must be taken to avoid
contamination of these items. Because of the risk of contamination with young children, it is prudent to choose a security
object that can be disposed as radioactive waste without causing great distress to the patient.

Nuclear Medicine Operations

Once the treating oncologist determines that a patient is a
candidate for 131I-MIBG therapy, the oncologist works with
the nuclear medicine staff to determine the dose of 131IMIBG to be administered and when the treatment will take
place. The nuclear medicine division then contacts the
appropriate radiopharmacy to order the required amount
of 131I-MIBG. The radiopharmacy should be informed as
soon as possible to ensure that adequate 131I-MIBG will be
available. At our institution, we routinely admit patients on
Monday and administer the 131I MIBG on Tuesday. The radiopharmaceutical should be ordered to be delivered as soon
as possible on the treatment day so that if there are any delays
in delivery, the radiopharmaceutical still can be administered
either later the same day or early the next day. All regulatory
and safety procedures must be followed for the administration of 131I. In the United States, this includes confirmation of
nonpregnancy (if appropriate) and the use of a signed written
directive that includes patient name, medical record number,
date of administration, and the amount, form and route of
administration.
At our institution, the radiopharmaceutical is received and
processed in the radiopharmacy of the nuclear medicine department. Typically, the 131I-MIBG is delivered frozen and
takes approximately one hour at room temperature to thaw.
Before administration, quality control testing must be performed to confirm that the free iodine is 10% of the total
131I in the vial. If this testing has been performed at the
radiopharmacy within 72 hours of administration, it may not
be necessary to repeat testing, although some research protocols may require onsite quality control testing of the radiopharmaceutical.
There are a variety of operational approaches for administering the 131I-MIBG. For our procedure, the 131I-MIBG is
drawn into a 30-mL syringe and, after the activity is assayed
in the dose calibrator, the syringe is placed in a shielded
syringe pump that is housed within an L-block shield on a
specially designed steel cart (Fig. 2). When the patient and
staff are ready for the administration, the dose is then transported to the therapy room on the cart. Before infusion, parents and nonessential caregivers are asked to leave the patients room to minimize their radiation exposure. 131I-MIBG

131I-MIBG

therapy of neuroblastoma

Figure 2 Shielded syringe pump. An example of a shielded syringe

pump used for administration of 131I-MIBG. The shielded syringe
pump (Graseby Injection Pump Shield, Biodex) is located behind an
L-block shield on a specially designed steel cart. The dose of 131IMIBG is drawn into a 30-mL syringe that is placed in the pump
before transport to the treatment room.

is administered through previously inserted and secured intravenous access; administration through an indwelling central line is preferable. With the assistance of the patients
nurse, the patency of the patients intravenous line is confirmed, and the syringe is attached by a Y-connector to the
intravenous line. Under the direction and monitoring of nuclear medicine staff, the 131I-MIBG is delivered to the patient
during 90-120 minutes. Once the administration is complete, the infusion apparatus is disconnected from the patients intravenous line and returned to the radiopharmacy,
where the residual/remaining dose is determined with the
dose calibrator.
At the end of the hospital stay (typically 3-5 days after
administration), the patient is brought to the nuclear medicine department for a posttherapy whole-body image to demonstrate the distribution of the administered activity. Static
images are acquired on the gamma camera for 300,000500,000 counts by the use of a high-energy collimator. During this short imaging session, it is advisable to keep adjacent
imaging rooms vacant to minimize radiation exposure to
other patients and staff.

Managing Radiation Exposure to Caregivers

The radiation safety program, under the direction of the radiation safety officer, is actively involved in planning and
implementing each therapy. Radiation safety staff helped
nursing managers develop guidelines for nursing contact
time using the principles of ALARA. All nursing staff and
family caregivers entering the patient room wear real-time
personal dosimeters, and all exposure is kept in a written log
placed at the door to the patient room. Family members not
actively involved in patient care are not allowed to enter the
treatment room. The use of real-time dosimeters has helped
both family caregivers and nurses proactively address ALARA
by monitoring the circumstances that specifically contribute

361
to exposures while not compromising essential patient care
or compassionate interactions during the isolation period.
Early in the program we used real-time dosimeters that functioned with an audible chirp, but once staff had developed
recognition and understanding with ALARA, these dosimeters have been used in silent mode. The staff and caregivers
also were trained to use a Geiger-Mueller based radiation
survey instrument that is located outside the therapy room to
verify that no personal contamination was present or being
tracked outside the controlled environment of the therapy
room.
Nurses and other hospital staff are provided thermoluminescent dosimetry-based radiation monitoring badges that
are changed monthly for the tracking and recording of occupational radiation exposures. In most cases, radiation exposures to individual nurses have been 1% of the 5 rem (50
mSv) allowable annual limit during a single patients stay,
although, in a few cases, a nurses exposure has reached 3% of
the allowable limit because of unique patient needs.
Caregivers are encouraged to leave the room whenever
possible and to not sleep in the patients room, although this
can be influenced by the patients medical needs, age, and
maturity. However, no specific time limits have been developed. Caregiver exposures typically are 10% of our allowable limit of 2 rem (20 mSv). Caregiver exposure will be
higher when there is only 1 family caregiver, but in all cases,
caregiver exposures have been 20% of the 2 rem (20 mSv)
limit. Most exposure occurs over the first 24 hours after infusion when the radiation levels are the highest. Management
of urine collection and disposal for catheterized patients is
one of the major exposure contributing tasks.
In the therapy room, bedside shields containing 2.5 cm
thick lead are used to limit exposure of family and nursing
caregivers. In patients with an indwelling bladder catheter,
the urine collection container is kept in a lead-shielded box.
The collection system has wheels so that it can be placed next
to the patients bed and then wheeled to the bathroom for
emptying.
Several of the 131I-MIBG clinical trial protocols required
the monitoring of radiation exposure levels from a fixed distance from the patient at predetermined time points. Thus,
we mounted an ion-chamber-based exposure meter at a fixed
location above the patient bed and recorded exposure and
entered into a spreadsheet. This system also is used to aid in
the determination of the patients discharge.

Radiation Containment and Disposal

Before the patient is admitted for 131I-MIBG therapy, radiation safety staff members prepare the patient room by covering floors, walls, and equipment with plastic covering to limit
contamination. After patient is discharged, all ancillary items
and equipment are stripped of any plastic covering and surveyed for both fixed and removable contamination. Room
fixtures and the floor are also stripped of their protective
coverings and surveyed in a similar fashion. The radiological
limits for allowable fixed and removable contamination for
releasing items and areas for unrestricted use are based on

S. Shusterman et al

362
criteria established during institutional licensing. Generally
regulatory guidance can be used to establish such limits, and
Regulatory Guide 8.23, Radiation Safety Surveys at Medical
Institutions provides surface contamination guidelines of
200 dpm/100 cm2 for I-131 and is based on license termination criteria found in U.S. Nuclear Regulatory Commission
Regulatory Guide 1.86. Typically, residual contamination
levels of 100 dpm/100 cm2 can be achieved, with the bathroom the only area needing decontamination. Ideally the
fixtures should be stainless steel rather than porcelain to minimize fixed contamination and facilitate decontamination
when necessary. Commonly available nonbleach containing
cleaning products usually are effective for surface decontamination. Items that cannot be decontaminated to acceptable
levels should be removed from the room and held for decay.
Waste materials, such as garbage, linens, laundry, and miscellaneous items should be segregated to limit the amount of
material requiring radioactive waste management. Contaminated items and materials should be held in storage for decay.
Decay storage space should be shielded or isolated to limit
any exposure in unrestricted areas and be well-ventilated as
waste and garbage that is held for months can be odorous.
Most therapy procedures generate 30-40 cu ft of waste during
the duration of the therapy. However, it can be difficult to
predict waste production, and waste storage capacity should
be large enough to store such items as beds and mattresses for
spills or patient accidents. Waste can be released once radiation levels have reached background levels.

Patient Discharge
For most patients, discharge timing is determined by radiation safety concerns. The day of discharge day can be predicted from previous experience with 131I-MIBG therapy.
Continuous patient exposure monitoring also can be used to
determine exposure rates and predict the timing of discharge.
In most cases, discharge depends on patient characteristics
and the administered activity and can occur 3-5 days after
administration. Criteria for discharge are determined by regulatory commitments made during the licensing process,
guided by Title 10 of the Code of Federal Regulations Part 35.
Licensees are permitted to authorize a release if the total
effective dose equivalent to any other individual from exposure to the released individual is not likely to exceed 0.5 rem
(5 mSv). It also requires the licensee to provide the released
individual (and family) with instructions on actions recommended to maintain doses to other individuals ALARA if the
total effective dose equivalent to any other individual is likely
to exceed 0.1 rem (1 mSv). This process should include interviews with parents regarding the circumstances that will
be encountered after release from the licensees control with
consideration of the mode of travel to home, length of travel,
living conditions, capability to maintain a high level of hygiene, capability to maintain a degree of continued isolation,
ability to limit contact to other sensitive groups or individuals, such as pregnant women and children. With pediatric
patients, other issues, such as the management of diapers,
exposure of siblings, and reestablishment of social activities

like school or daycare can complicate discharge planning.

The specific instructions provided to each patient should
address their unique situation and clearly identify how patients and caregivers can minimize exposures to others and
limit any concerns of contamination. Instructions should be
written and reviewed in detail before release and the licensee
should retain a signed copy of the instructions that indicate
the patient or guardian has read and understands these instructions. For those traveling by commercial carrier or
across borders during the three months following treatment,
instructions should provide enough information that law enforcement can confirm the medical nature of any radiation
that may be detected.

Conclusions
131I-MIBG therapy can be an effective and well-tolerated ther-

apeutic approach for neuroblastoma. Most studies have assessed its utility in patients with recurrent or relapsed disease, but it also may hold promise for use earlier in the course
of therapy. Developing an MIBG therapy program requires
extensive planning and commitment of institutional resources. Successful implementation of a program depends on
effective collaboration and communication among a broad
range of disciplines, active involvement of the patient and
family, and ongoing education and training of all caregivers.

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