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Intra-Arterial Chemotherapy for Retinoblastoma: A Collaborative Effort

Article  in  Journal of Radiology Nursing · January 2018

DOI: 10.1016/j.jradnu.2017.12.001

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Journal of Radiology Nursing

journal homepage: www.radiologynursing.org

Intra-Arterial Chemotherapy for Retinoblastoma: A Collaborative

Effort
Floreen Knight, BSN, RN, CPN a, Kathleen Stiffler, CPNP, CPON b,
Colleen Nixon, MSN, RN, CPHON c, Debra Lajoie, PhD, MSN, RN d,*
a
Interventional Radiology Boston Children's Hospital, Boston, MA
b
Hematology/Oncology, Boston Children's Hospital, Boston, MA
c
Hematology/Oncology Boston Children's Hospital, Boston, MA
d
Surgical Programs, Boston Children's Hospital, Boston, MA

a b s t r a c t

Keywords: Approximately 300 children in the United States are diagnosed yearly with retinoblastoma. For a gen-
Intra-arterial chemotherapy eration, it has had the highest cure rate among pediatric solid tumors, allowing reduction in side effects
Retinoblastoma of management to become important determinants of therapy. Priorities of treatment are saving life,
Pediatrics
eyes, and vision. Standard treatment involves enucleation, multiagent systemic chemotherapy, and ra-
Radiology nursing
diation and intra-arterial chemotherapy (IAC). IAC is a treatment option to deliver chemotherapy locally
to the eye while minimizing systemic exposure. Research in the treatment of retinoblastoma has led to
new treatment protocols for children. The purpose of this article is to define retinoblastoma, introduce
the goals and priorities of retinoblastoma treatment, and describe the standard of care treatment options
with a focus on IAC, which is administered in interventional radiology. It also highlights important
nursing issues including the administration of chemotherapy in a clinical area where it is not tradi-
tionally administered and the challenges faced in caring for children and families with retinoblastoma.
Copyright © 2017 Published by Elsevier Inc. on behalf of Association for Radiologic & Imaging Nursing.

Introduction American descent in North America (Rodriguez-Galindo et al.,

Retinoblastoma is the most common malignant primary intra-
ocular tumor that arises in the retina and accounts for approxi-
mately 3% of all worldwide pediatric cancers (Efren, Monroy,
Orbach, & Vanderveen, 2014; Rodriguez-Galindo, Orbach, & Van-
derVeen, 2015). It is a cancer seen most often in very young chil-
dren, as two-thirds of all cases are diagnosed before 2 years, and is
rarely seen in children older than 5 years (Rodriguez-Galindo et al.,
2015). Retinoblastoma has a 95% survival rate in the United States,
which has allowed for the evolution of disease management toward
a more risk-adapted approach, with the goal to optimize saving
lives, eyes, and vision while minimizing short-term and long-term
toxicities (Rodriguez-Galindo et al., 2015). In less developed coun-
tries where there is greater tumor burden, reported survival rates
remain as low as 0% to 5% (Singh & Daniels, 2016). The incidence of
retinoblastoma is disproportionally distributed around the world
with higher rates found in Africa, India, and in children of Native
* Corresponding author: Debra Lajoie, Surgical Programs, Boston Children's
Hospital, 300 Longwood Avenue, 10 NW, Boston, MA 02115.
E-mail address: debra.lajoie@childrens.harvard.edu (D. Lajoie).
2015).
Intra-arterial chemotherapy (IAC) is a treatment option for
retinoblastoma that is improving ocular survival and visual acuity,
with fewer and less severe systemic complications than systemic
chemotherapy or external beam radiation (EBR) (Efren et al., 2014).
The purpose of this article is to define retinoblastoma, introduce the
goals and priorities of retinoblastoma treatment, and describe the
standard of care treatment options with a focus on IAC, which is
administered in interventional radiology (IR). It also highlights
important nursing issues including the administration of chemo-
therapy in a clinical area where it is not traditionally administered
and the challenges faced in caring for children and families with
retinoblastoma.
IAC requires a well-coordinated multidisciplinary approach to
assure safe delivery of chemotherapy in a nononcology setting.
These children require frequent evaluations by oncology ophthal-
mologists, pediatric oncologists, pediatric neurointerventional ra-
diologists, anesthesiologists, interventional radiologists, oncology
registered nurses (RNs) and nurse practitioners, and psychosocial
providers. The multidisciplinary team approach is critical to mini-
mize the inherent risks of delivery of chemotherapy in a non-
oncology setting, such as chemotherapy errors, and minimize risks

https://doi.org/10.1016/j.jradnu.2017.12.001
1546-0843/$36.00/Copyright © 2017 Published by Elsevier Inc. on behalf of Association for Radiologic & Imaging Nursing.
2 F. Knight et al. / Journal of Radiology Nursing xxx (2017) 1e6
of the IR procedure itself, including stroke and bleeding (Efren et al.,
2014). At Dana Farber/Boston Children's Cancer and Blood Disorders
Center, IR and oncology nurses assume a leadership role in this
process.
Pathogenesis
The pathogenesis of retinoblastoma involves the inactivation of
both alleles on the RB1 gene, allowing for tumors to develop. There
are two clinical forms of retinoblastoma. Heritable retinoblastoma
is defined by the presence of a germ line mutation of the RB1 gene,
which may have been inherited (25%) or occurred as a de novo
mutation early in embryogenesis (Rodriguez-Galindo et al., 2015).
Children with the heritable form are typically diagnosed at an early
age (median time to diagnosis, 14e16 months) and present with
bilateral or unilateral multifocal disease (Rodriguez-Galindo et al.,
2015). Children with an RB1 germ line mutation may continue to
develop new tumors after diagnosis and treatment and need
frequent examinations for years (Rodriguez-Galindo et al., 2015).
These children are also at a higher risk to develop secondary ma-
lignancies later in life, secondary to their germ line mutation, and
this risk increases after treatment with radiation and chemotherapy
(Rodriguez-Galindo et al., 2015). The nonheritable form is defined
by a sporadic mutation to both alleles in a somatic cell. Children
with this form typically present at an older age (median time to
diagnosis, 29e30 months) and present with unilateral unifocal
disease. They are not at risk to develop secondary malignancies
later in life (Rodriguez-Galindo et al., 2015). All children with reti-
noblastoma are referred for genetic counseling to assist parents in
understanding the genetic consequences of each form of retino-
blastoma, estimate the risk in relatives, and test for the presence of
a germ line mutation (Rodriguez-Galindo et al., 2015).
Early detection of retinoblastoma is critical to the treatment
options as it allows for identification of the disease while it is still
intraocular (Rodriguez-Galindo et al., 2015). There are a variety of
treatment options for retinoblastoma, including several vision-
sparing therapies (Rodriguez-Galindo et al., 2015). Factors influ-
encing treatment choice are the tumor size and location, visual
prognosis, the presence or the absence of vitreous or retinal seeds,
age and genetic status (Rodriguez-Galindo et al., 2015). Treatment
options include enucleation, focal therapies (cryotherapy and
laser), radiation therapy (EBR or proton beam), systemic chemo-
therapy, IAC, and intravitreal chemotherapy (Rodriguez-Galindo
et al., 2015). A review of the literature shows that treatment for
retinoblastoma, especially bilateral disease, has evolved to be more
focused on globe salvage and some vision preservation.
Although the first report of IAC was in 1958, Gobin, Dunkel,
Marr, Brodie, and Abramson (2011) began using selective
ophthalmic artery infusion in 2006 at their institution and with a
decade of experience have shown that IAC could be successful in
avoiding enucleation and EBR therapy, with acceptable ocular
toxicity and minimal systemic side effects (Efren et al., 2014; Gobin
et al., 2011). In Gobin center, they have replaced systemic chemo-
therapy and EBR, both of which have many potentially serious
adverse effects, with IAC for tumors too large to be controlled with
focal therapies alone (Gobin et al., 2011). Gobin et al. (2011) re-
ported that catheterization succeeded in 98.5% of all procedures.
Ocular event-free survival rates at 2 years were 70% for all eyes,
81.7% for eyes that received IAC as their primary treatment, and
58.4% for eyes that had previous treatment with chemotherapy or
EBR (Gobin et al., 2011).
Munier et al. (2017) compared outcomes of advanced unilateral
disease treated with systemic chemotherapy to first-line IAC. Globe
retention was 100% in the IAC group as compared with 57% in the
systemic chemotherapy group. No metastasis or deaths occurred in
either group, and IAC was associated with fewer side effects, faster
and more extensive response rates, fewer relapses, and better visual
acuity than the systemic chemotherapy group. They concluded that
IAC should be considered the treatment of choice in Group D
unilateral retinoblastoma (Murphree, 2005; Rodriguez-Galindo
et al., 2015). Abramson, Marr, and Francis (2016) performed a
single-institution retrospective study of all Group D eyes treated
with IAC from 2006 to 2012. This study concluded that IAC is a very
effective treatment for Group D retinoblastoma and appears to have
rates of globe salvage much greater than systemic chemotherapy
without compromising patient survival (Abramson et al., 2016). IAC
can be performed multiple times, using multiple chemotherapeutic
agents on one or both eyes, with an acceptable side-effect profile
(Abramson et al., 2016).
IR Procedure
Performing neuroradiology interventions in children necessi-
tates a well-orchestrated team approach to ensure patient safety
and optimal patient outcomes. Nurses take the lead on facilitating
communication across the care team. Members of the multidisci-
plinary team need to have a shared understanding of the inherent
risks. Because retinoblastoma is a disease of young children, the
unique neurovascular anatomy and physiology of these children
make neuroradiology procedures more challenging than in adults.
It is critical that steps be taken to mitigate the risks that pediatric
neurointerventional procedures present (Ashour & Orbach, 2015).
These types of neurointerventional procedures require total
patient immobility and are done under general anesthesia using
paralytics with the anesthesia team providing breath holding as
needed. Systemic anticoagulation is typically administered to
decrease the potential risk of thromboembolytic stroke or ischemic
injury (Rodriguez-Galindo et al., 2015). In addition, obtaining
femoral arterial access in a small child may increase the risk of
lower extremity ischemic complications. Therefore, the smallest
possible femoral sheath is used for arterial access. Because of lim-
itations in the amount of contrast that can be given based on the
child's weight, the neuroradiologist must be judicious with contrast
administration (Orbach et al., 2014).
IAC is performed under fluoroscopic visualization so these pa-
tients are unavoidably exposed to ionizing radiation. There is
increasing evidence that children are more vulnerable and have an
increased risk of developing secondary tumors (Orbach et al., 2014).
Optimized radiation exposure techniques are used by the neurora-
diologist whenever possible. As the use of IAC for pediatric retino-
blastoma emerged, we were additionally challenged to develop an
interdisciplinary process to support the management of chemo-
therapy in IR where chemotherapy was not traditionally delivered.
This required developing a strong collaboration between IR and
oncology nurses within our institution to ensure patient safety.
Before scheduling IAC, an eye examination that includes a
complete ophthalmoscopic examination, an ultrasound to deter-
mine tumor dimensions, and an electroretinogram are performed
in a separate procedure under general anesthesia. An electroreti-
nogram measures the electrical activity of retina in response to
stimulation. Local treatment using cryotherapy (cold) and or laser
(heat) is often required and administered by the ophthalmologist
during each eye examination under anesthesia (EUA), beginning
with the first course of chemotherapy. The local therapy given will
depend on the tumor size and location (Rodriguez-Galindo et al.,
2015). This local therapy is standard in the treatment of retino-
blastoma (Rodriguez-Galindo et al., 2015). The need for local
treatment is determined by the interdisciplinary medical team.
Local treatment is used in combination with chemotherapy and
appears to have a synergistic effect in treating retinoblastoma
 F. Knight et al. / Journal of Radiology Nursing xxx (2017) 1e6 3

(Rodriguez-Galindo et al., 2015). After completion of chemotherapy,
it is expected that more local therapy will be needed for any tumors
that have not completely gone away and/or for new small tumors
that often develop. These examinations provide a baseline for
evaluation of tumor regression after the IAC procedure. Figure 1
shows the pre-IAC magnetic resonance imaging (MRI). The IAC is
then scheduled to be done in the IR suites by a neurointerventional
radiologist.
In preparation for the IAC procedure, the patient and family are
scheduled to be seen in the oncology clinic, and the individual
treatment plan is reviewed and consent for the chemotherapy is
obtained. This visit is typically done 1 to 2 days before the pro-
cedure and includes a physical examination, obtaining any neces-
sary blood work, and placement of the chemotherapy orders. The
chemotherapy orders are then reviewed by chemotherapy-
competent pharmacists and chemotherapy-competent nurses
before the procedure.
On the day of the procedure, the IR nurse performs a pre-
procedural assessment; reviews laboratory results and completes a
preprocedural checklist. Separate consents are obtained for both
the procedure and the anesthesia. The chemotherapy consent and
individual treatment plan are also reviewed. Any discrepancy is
resolved before the initiation of the procedure.
The patient is then brought to the procedure room, and the team
performs a sign in that includes verification of the patient, the
patient's weight, allergies, and the intended procedure. The
anesthesiologist proceeds with oral intubation for the initiation of
general anesthesia. The anesthesiologist then administers dexa-
methasone intravenously at induction. In addition, albuterol is
given via the endotracheal tube, and oxymetazoline is given in the
nostril ipsilateral to the tumor to decrease blood flow to the nose
via the ophthalmic artery ethmoidal branches. After performing a
time-out, the neurointerventional radiologist will place a sheath
into the femoral artery using ultrasound guidance, and the patient
will be systemically heparinized with a target activated clotting
time (ACT) of 200 to 350. The patient will undergo a cerebral
angiogram via the internal carotid artery on the same side as the
tumor (Figure 2). Subsequently, the ophthalmic artery is cannulated
by the neuroradiologist under fluoroscopic guidance using a
microcatheter and standard neurointerventional technique. If the
retinoblastoma is bilateral, each internal carotid artery will be
catheterized.
Chemotherapy
Melphalan is the most frequently used chemotherapy drug in
IAC for retinoblastoma (Efren et al., 2014; Rodriguez-Galindo et al.,
2015). The globe is disproportionally large at birth reaching nearly
adult size in infancy. Therefore, dosing is based on the perfused
arterial volume of the target organ rather than by the patient's body
weight or surface area (Rodriguez-Galindo et al., 2015). Typically,
three fixed doses of melphalan are administered: 5 mg for patients

Figure 1. Magnetic resonance imaging. Left globe filled with tumor (green arrow). ICA ¼ internal carotid artery (solid red arrow); OA ¼ ophthalmic artery (dashed red arrow). (For
interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
4 F. Knight et al. / Journal of Radiology Nursing xxx (2017) 1e6
Figure 2. Cerebral angiogram (pretreatment). ICA ¼ internal carotid artery (solid red arrow); OA ¼ ophthalmic artery (dashed red arrow). (For interpretation of the references to color
in this figure legend, the reader is referred to the Web version of this article.)
older than 24 months, 4 mg for patients 12 to 24 months, and 3 mg
for patients younger than 12 months (Rodriguez-Galindo et al.,
2015). The melphalan is diluted in saline and administered by the
neurointerventional radiologist in a pulsatile injection during 10 to
15 min. The pulsatile injection is designed to minimize streaming of
the injection because of laminar flow and promote uniform de-
livery. In addition to melphalan, topotecan or cisplatin may be
added as a second IAC agent in patients with advanced disease and
is administered by the same technique (Rodriguez-Galindo et al.,
2015).
The challenge, at our institution, was to develop a multidis-
ciplinary approach to assure safe delivery of chemotherapy in a
nononcology setting. This required close collaboration and
communication between the IR nurse and the chemotherapy-
competent nurses to verify chemotherapy orders were checked
per hospital policy. It was also essential to ensure that all IR
staff received education to provide a safe level of care for the
patient, and reduce employee exposure to cytotoxic agents. This
education focused on the type of chemotherapy being admin-
istered, side effects of the drug, as well as safe handling (use of
personal protective equipment) and disposal of chemothera-
peutic drugs. Online education modules were assigned to all
staff, and additional education by the oncology nurse educator
was provided.
In advance of the procedure, the inpatient oncology charge
nurse receives notification that an IAC procedure is scheduled in IR,
and the chemotherapy orders are checked. On the day of the pro-
cedure, the IR nurse confirms the melphalan order. The oncology
pharmacy is notified to begin the preparation of the melphalan or
other chemotherapy ordered when the neurointerventional radi-
ologist indicates that he is approaching cannulation of the
ophthalmic artery. Melphalan needed to be administered within
1 hr of reconstitution but newer preparations of the drug now have
an expiration time of 4 hr. However, some of the chemotherapy
agents still must be administered within 1 hr of preparation. The IR
nurse then notifies the oncology charge nurse when the radiologist
is ready to administer the chemotherapy. The inpatient
chemotherapy-competent nurse obtains the chemotherapy drug
from the oncology pharmacy and delivers it to the IR suite for
verification before administration. The chemotherapy drug is veri-
fied with the chemotherapy order in the IR suite and signed off in
the electronic medical record by two RNs (one being chemotherapy
competent). When the chemotherapy is delivered to the neuro-
interventional radiologist, a safety pause is performed by restating
the patient's name, medical record number, allergies, and a
reconfirmation of the drug, dosage, and expiration date.
Once the chemotherapy has been administered, the IR nurse will
recheck the ACT. At our institution, the neuroradiologist typically
waits until the ACT is less than 200 before removing the femoral
artery sheath to reduce the risk of femoral artery bleeding or he-
matoma. After the sheath is removed, a pressure dressing is applied,
and the patient is then extubated and transferred to the post-
anesthesia care unit. Postprocedure care includes flat bed rest for
4 hr, standard postangiography groin checks for bleeding, neuro-
logical checks, pain management, and an assessment of any adverse
ocular symptoms. It can be difficult to maintain flat bed rest for a
 F. Knight et al. / Journal of Radiology Nursing xxx (2017) 1e6
Figure 3. Ultrasound: before and after IAC. IAC ¼ intra-arterial chemotherapy. The solid red arrows are tumor margins- pre and post IAC to demonstrate the change in size after 2
rounds of IAC.
young child for a 4-hr period, and occasionally, the anesthesiologist
may order sedation to help the child remain quiet. The child is
typically discharged on the day of procedure with a follow-up visit
in 1 week in the oncology clinic. Families are given discharge in-
structions with specific instructions to avoid strenuous exercise and
maintain the femoral groin dressing until the next morning. There
are limited data available for IAC melphalan toxicity. Side effects are
usually minimal with some reports of lid edema, conjunctivitis, and
mild neutropenia. Serious side effects such as death or stroke have
not been reported (Efren et al., 2014).
The patient generally receives three treatments of IAC with 3- to
4-week intervals between treatments, but up to six treatments may
be needed for total eradication of the tumor (Rodriguez-Galindo et
al., 2015). The patients are followed by ophthalmic examination to
document tumor regression and calcification between each IAC
treatment and after therapy is completed (Figure 3).
Case Presentation
This case summary is representative of the population of chil-
dren who have received this type of therapy within our program.
This previously healthy 2-year-old female was diagnosed with
unilateral retinoblastoma after her father noted a golden hue in her
right eye. Her primary pediatrician referred her to an ophthal-
mologist who was able to confirm the tumor in her right eye. She
lived at home with her parents and older brother and had no family
history of retinoblastoma or other malignancies. An EUA revealed
an intraocular tumor. The base of the tumor was inferior to the optic
nerve with shallow retinal detachment peripherally. No vitreous
seeding was noted, although traces of vitreous cells were seen. Her
left eye was normal. Her workup included an MRI of the brain and
orbits as well as blood work. Except for the change in eye color, the
family did not notice any other changes in her vision. The patient's
disease was classified as right-sided Group D. Group D tumors are
classified using the International Classification for Intraocular
Retinoblastoma definitions (Murphree, 2005; Rodriguez-Galindo
et al., 2015). Per this classification system, Group D tumors have
diffuse subretinal fluid or seeding (Murphree, 2005; Rodriguez-
Galindo et al., 2015).
The probability that there was a genetic component to her dis-
ease was low because her retinoblastoma had presented
5
unilaterally and was diagnosed at an age older than 2 years. Despite
this, our practice is to refer all children with retinoblastoma for
genetic counseling to test for the presence of a germ line mutation.
Based on the grouping and tumor involvement, there were three
treatment options discussed with the family: enucleation, systemic
chemotherapy, and IAC. The risk factors that needed to be consid-
ered in the treatment decision to cure this patient included the
patient's age, stage and extent of disease, and the potential to
maintain vision. The treatment plan for this patient was to receive
three to four cycles of intra-arterial melphalan with a repeat EUA
before each scheduled therapy to evaluate response. She received
four courses of IA melphalan chemotherapy with few treatment
side effects, displaying minimal signs of bone marrow suppression.
She continues to follow-up in the outpatient oncology clinic and
undergoing EUA to monitor disease status.
Summary
IAC is a treatment option with potentially less devastating side
effects and can be highly effective at achieving eye salvage. As IAC is
an emerging treatment modality, more research needs to be done,
especially in relation to radiation exposure during fluoroscopy and
the risk of developing secondary malignancies. IAC requires a well-
coordinated multidisciplinary approach to assure safe delivery of
chemotherapy in a nononcology setting. In collaboration, IR and
oncology nurses have the knowledge and skills to assume a lead-
ership role in the process.
Acknowledgments
The authors gratefully acknowledge the following individuals
for their contributions to this article: Carlos Rodriguez-Galindo,
MD, St. Jude's Hospital, Memphis, TN and Darren Orbach, MD,
Boston Children's Hospital, Boston, MA. Photographs courtesy of
Darren Orbach, MD.
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group D retinoblastoma. PLoS One, 11(1), 1-13.
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