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Hyperfractionated External Beam Radiation Therapy in the Treatment of Murine Transgenic Retinoblastoma
Brandy C. Hayden, BS;
Timothy G. Murray, MD;
Nicole Cicciarelli;
Ingrid U. Scott, MD, MPH;
Anastassia Alexandridou, MD;
Eleut Hernandez, LAT;
Xiaodong Wu, PhD;
Arnold M. Markoe, MD;
William Feuer, MS;
Lilia Fulton, BA;
Joan M. O'Brien, MD
Arch Ophthalmol. 2002;120:353-359.
ABSTRACT
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Objective To determine the in vivo efficacy of hyperfractionated external beam
radiation therapy (EBRT) in comparison with standard daily EBRT in a murine
model of heritable retinoblastoma.
Methods Two hundred twenty eyes from 6-week-old simian virus-40 large T-antigen–positive
mice were treated with a total dose of EBRT ranging from 10-76 Gy (1000 to
7600 rad). One hundred ten eyes underwent EBRT administered in 2.0-Gy (200-rad)
fractions once per day. Forty-two eyes received hyperfractionated EBRT administered
in 1.2-Gy (120-rad) fractions twice per day, while 48 eyes received EBRT twice
daily in fractions of 5.0 Gy (500 rad). Twenty eyes served as untreated controls.
All eyes were obtained for histopathologic examination and graded positive
if any tumor was present.
Results A dose-dependent inhibition of ocular tumor was observed for EBRT in
these transgenic retinoblastoma mice. The tumor control dose for 50% of eyes
(TCD50) treated with 2.0 Gy fractions of EBRT was 45 Gy (4500 rad)
when treatments were administered once daily. A significant increase in tumor
control was observed when treatments were administered twice per day at fractions
of 1.2 Gy, resulting in a TCD50 of 33 Gy (3300 rad) (P = .003). A further increase in tumor control was observed when twice-daily
EBRT was administered in 5.0 Gy fractions resulting in a TCD50
of 28 Gy (2800 rad).
Conclusions Hyperfractionated EBRT safely and effectively controls intraocular retinoblastoma
in this transgenic animal model. Use of hyperfractionation allows for a reduction
in total radiation delivered dose, while shortening the total treatment time.
Clinical Relevance This treatment approach may be applicable in the management of pediatric
retinoblastoma by maintaining excellent tumor control, while reducing treatment-associated
complications.
INTRODUCTION
RETINOBLASTOMA, arising from embryonic photoreceptor cells in the eye,
is the most common primary intraocular malignancy in childhood.1-2
Children with a germline RB gene mutation are predisposed
to bilateral eye involvement and a lifetime predilection for cancer involvement.3-5
Recent evidence suggests an increase in the incidence of retinoblastoma
during the last 40 years, possibly because of more successful methods of treatment
resulting in improved patient survival and/or increased mutation rates.6 Current treatment methods include enucleation, scleral
plaque irradiation, cryotherapy, photocoagulation, external beam radiotherapy
(EBRT), chemotherapy, and combined therapeutic modalities.2, 7-8
Retinoblastoma is a highly radiosensitive tumor and can be effectively
treated with ionizing EBRT.9-11
In the past, EBRT was administered most commonly to children with bilateral
retinoblastoma that was untreatable with local therapies.12
This treatment modality was generally preferred if a tumor was larger than
15 mm in diameter, if it was located adjacent to the optic disc or fovea,
if multiple tumors were present, or if extensive vitreous seeding of tumor
cells was noted.9 Failures of EBRT leading
to enucleation were often due to progression of vitreous seeds, recurrences
from previously existing tumors, or the development of new intraocular tumors.13
Although EBRT has been shown to improve ocular and visual prognosis
in retinoblastoma survivors, it is associated with multiple complications.14-18
Current concerns related to the application of radiotherapy in the treatment
of retinoblastoma have focused on delayed complications including radiation-enhanced
second tumor risk for children with RB1 germline
mutations, radiation related midface hypoplasia, cataract and, rarely, radiation
vasculopathy or optic neuropathy.19-21
Hyperfractionated radiotherapy may offer the potential for effective
treatment, while minimizing toxicity and lowering the risk of secondary malignancy.
Hyperfractionated radiotherapy involves the delivery of an increased number
of fractional radiation doses of smaller than conventional size in an overall
treatment time comparable with, or shorter than, that required for conventional
EBRT.22 It has demonstrated increased tumor
control in other pediatric tumors.23-25
Studies of pediatric acute myeloblastic leukemia demonstrated that tumor control
could be achieved at lower total treatment doses when twice vs once-daily
treatment was used. 26-28
Hyperfractionated radiation therapy was also found to be effective in the
treatment of medulloblastoma, ependymomas, and rhabdomyosarcoma.25, 29-33
In the current study, a transgenic mouse model of heritable retinoblastoma
was used to evaluate the in vivo efficacy of twice-daily hyperfractionated
EBRT (1.2- and 5.0-Gy [120- and 500-rad] fractions) compared with treatment
delivered once per day (2.0-Gy [200-rad] fractions).
MATERIALS AND METHODS
The study protocol was approved by the University of Miami School of
Medicine Animal Care and Use Review Board, Miami, Fla. All experiments in
this study were conducted in accordance with the Association for Research
in Vision and Ophthalmology guidelines for the use of animals in ophthalmologic
and vision research.
Two hundred twenty simian virus-40 large T-antigen transgene-bearing
mice were treated, as described below, beginning at 6 weeks of age. Transgenic
animals were identified through polymerase chain reaction analysis of tail
DNA. Transgene-positive animals develop bilateral, heritable retinoblastoma
that resembles human retinoblastoma. All animals were anesthetized with a
combination of intraperitoneal ketamine hydrochloride and xylazine hydrochloride
and topical proparacaine hydrochloride for the purpose of tail blood extraction.
No anesthesia was required for EBRT.
ORBITAL EBRT
Two hundred twenty mouse eyes were treated, as described herein, with
fractionated EBRT with the use of a 10-mV x-ray machine (Clinac-2100; Varian
Medical Systems, Inc, Palo Alto, Calif). Animals were briefly immobilized
for treatment in specially constructed cages and shielded to minimize radiation
to the midline nonocular structures (Figure
1). Animals were placed, head first, in the immobilization tube,
treatment ports were confirmed, and radiation was delivered at 3.24 Gy/min
(324 rad/min) to a field size of 7.0 x 7.0 cm, with the heads of 4 mice
radiated simultaneously. This treatment effectively focuses therapy to the
orbit, while shielding nonocular midline structures. The total treatment doses
ranged from 24-76 Gy (2400 to 7600 rad).
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Figure 1. Midline shielding and immobilization
apparatus for orbital external beam radiation therapy.
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One hundred ten eyes underwent EBRT administered in 2.0-Gy fractions
delivered once per day, 5 days per week. Forty-two eyes received EBRT twice
per day, 5 days per week, in fractions of 1.2 Gy, while 48 eyes received similar
treatment in fractions of 5.0 Gy. All radiation treatments delivered twice
per day were administered 6 to 8 hours apart. An additional 20 eyes from simian
virus-40 T-antigen–positive transgenic mice served as untreated controls.
HISTOPATHOLOGIC STUDY OF TRANSGENIC MICE
At 16 weeks of age, all animals were killed with an overdose of ketamine
and xylazine. Both eyes were enucleated and immediately immersion-fixed in
10% formalin. The eyes were sectioned serially with 80-µm sections stained
with hematoxylin-eosin. Light microscopic examination was performed on all
histopathologic sections in a masked fashion. The eyes were graded positive
for tumor development if any histopathologic evidence of tumor was present.
Eyes were also evaluated for evidence of corneal, lenticular, retinal, or
scleral toxic effects.
STATISTICAL ANALYSIS
To determine the dose-response relationships among the different EBRT
fractionation schemes, the data from all experimental groups were combined
and subjected to probit statistical analysis. Total radiation dose was entered
as a linear predictor in a maximum likelihood probit regression model. The
model was analyzed for goodness-of-fit, and logistic regression analysis was
used to estimate the relationship between EBRT dose and tumor control.
RESULTS
All untreated control eyes exhibited large intraocular tumors (Figure 2). None of the eyes treated with
a total radiation dose below 10 Gy (1000 rad) exhibited tumor control (Table 1).
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Figure 2. Enucleated globe of a 16-week-old
transgenic retinoblastoma mouse that received no treatment (control). Note
large retinal tumor (original magnification x7).
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Tumor Response for Each Subgroup of Conventional Single-Daily and Hyperfractionation
Twice-Daily Therapy at Each Dose Fraction*
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A dose-dependent inhibition of ocular tumor was observed for EBRT in
these transgenic retinoblastoma mice at all treatment fractions and dosing
strategies. Increasing the frequency of radiation treatment, while decreasing
the fraction delivered per treatment, was significantly associated with increased
tumor control when 1.2 Gy hyperfractionation was compared with 2.0 Gy conventional
daily fractionation (Figure 3 and Figure 4). The tumor control dose for 50%
of the eyes (TCD50) treated once daily with 2.0 Gy fractions was
45.0 Gy (4500 rad) at 16 weeks of age. The tumor control dose decreased to
33.9 Gy (3390 rad) for animals treated with radiation in 1.2-Gy fractions
twice per day. Increasing the fractionated dose from 1.2-Gy to 5.0-Gy fractions
twice per day further increased tumor control, resulting in a TCD50
of 28.0 Gy (2800 rad). However, corneal and lenticular damage was observed
in all of the eyes treated with these high-dose fractions of 5.0 Gy (Figure 5). None of the animals treated with
dose fractions of either 2.0 or 1.2 Gy showed evidence of toxicity.
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Figure 3. Enucleated globes of transgenic
mice after receiving external beam radiotherapy in 2.0-Gy (200-rad) fractions
once per day. All eyes were enucleated at 16 weeks of age. A, Eye treated
with a total dose of 24.0 Gy (2400 rad). Note that a large tumor is present.
B, Eye treated with a total dose of 36.0 Gy (3600 rad). A moderate-sized tumor
is present. C, Eye treated with a total dose of 48.0 Gy (4800 rad). Microscopic
tumor is present. Note that no evidence of cataract, scleral thinning, corneal
decompensation, or retinal abnormality is present (original magnification
x7).
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Figure 4. Enucleated globes of transgenic
mice after receiving external beam radiotherapy in 1.2-Gy (120-rad) fractions
twice per day. All eyes were enucleated at 16 weeks of age. A, Eye treated
with a total dose of 24.0 Gy (2400 rad). A small tumor is present. B, Eye
receiving a total radiation dose of 33.6 Gy (3360 rad). Note the presence
of microscopic tumor. C, Eye treated with a total dose of 48.0 Gy (4800 rad).
Complete absence of tumor is demonstrated. No evidence of cataract or other
toxic effect is present (original magnification x7).
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Figure 5. Enucleated globes of transgenic
mice after receiving external beam radiotherapy in 5.0-Gy (500-rad) fractions
twice per day. All eyes were enucleated at 16 weeks of age. A, Eye treated
with a total dose of 20.0 Gy (2000 rad). Note that trace tumor is present.
B, Eye treated with a total dose of 30.0 Gy (3000 rad). Note complete absence
of tumor. C, Eye treated with a total dose of 50.0 Gy (5000 rad). Note complete
absence of tumor. Evidence of cataract, scleral thinning, and corneal decompensation
are present (original magnification x7).
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Probit regression analysis was used for estimating the relationship
between dose and tumor control, and logistic regression analysis demonstrated
that the dose-response curves were significantly different among the 3 treatment
groups (P = .003) (Figure 6).
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Figure 6. External beam radiation dose-response
curves using probit analysis demonstrating the proportion of tumor-containing
eyes controlled by fractionated radiation treatments by total treatment dose.
Increasing treatment frequency from 2.0 Gy once daily to 1.2 Gy twice daily
is associated with increased tumor control with a reduction in the tumor control
dose for 50% of eyes. Tumor control can be further increased with the use
of 5.0-Gy fractions twice daily; however, this dose is relatively toxic and,
therefore, not clinically relevant. To convert gray to rad, multiply by 100.
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COMMENT
External beam radiation therapy has been used for the treatment of retinoblastoma
for more than 50 years. Focal delivery to the eye, new megavoltage machines,
and lens-sparing techniques have contributed to the increasing efficacy of
this treatment modality, improving ocular and visual prognoses, while decreasing
treatment-related morbidities.34 The current
study demonstrates that hyperfractionation (increasing the frequency of radiation
treatment, while decreasing the fraction delivered per treatment) is significantly
associated with increased tumor control in a murine transgenic model of retinoblastoma.
A wide range of EBRT dose fractionation schedules have been used previously
in the management of childhood retinoblastoma; however, the choice has been
largely empirical.13, 35-36
Treatment variables have recently become more defined, with the most common
fractionation schemes using fractions ranging from 1.8 Gy (180 rad) to 2.0
Gy administered once per day with total doses not exceeding 50.0 Gy. Radiation
fractions greater than 2.0 Gy per treatment are potentially associated with
severe ocular and periocular morbidity, particularly in eyes receiving concomitant
chemotherapy. Total radiation doses exceeding 45.0 Gy may lead to lacrimal
gland damage and decreased tear production. At total doses exceeding 50.0
Gy, radiation retinopathy may be seen.37
Despite the recent development of more defined treatment schedules,
optimal dose-fractionation schedules are still unclear. The use of this unique
mouse model of retinoblastoma has allowed for preclinical modeling of a variety
of treatment regimens. As reported previously, the transgenic mouse model
used in this study has histopathologic, immunocytochemical, electron microscopic,
and clinical characteristics similar to those of human retinoblastoma. 38-41 In
addition, the course of tumor development parallels that of human retinoblastoma.
Hyperfractionated radiotherapy refers to the delivery of an increased
number of fractional radiation doses of smaller than conventional size in
an overall treatment time comparable to, or shorter than, that required for
conventional EBRT.22 Hyperfractionation is
usually accomplished by delivering more than 1 fraction per day in sessions
ranging from 4 to 8 hours apart. The rationale underlying the application
of hyperfractionation is to exploit the differential radiosensitivities of
the target volume tissues showing acute effects from those showing late effects,
to decrease the rate of complications, while improving local tumor control.22 Radiosensitivity is related inversely to the degree
of differentiation of the tissue and directly related to mitotic and mitochondrial
activity.37 Although retinoblastoma has been
characterized as a moderately well-differentiated tumor, it may be particularly
susceptible to hyperfractionated EBRT because of the tumor's high mitotic
activity.
A phase 1/2 study was conducted to investigate the efficacy and toxicity
of hyperfractionated radiotherapy in 136 children with poor-prognosis brainstem
tumors.30 Children with brainstem tumors were
treated with hyperfractionated EBRT at 1.1 Gy (110 rad) twice daily (minimum
of 4-6 hours between fractions) to 66.0 Gy (6600 rad) in 6 weeks. Most patients
(71% [24/34]) improved clinically during the course of treatment. This prompted
a dose escalation from 66.0 Gy to 70.2 Gy (7020 rad) and then to 75.6 Gy (7560
rad).31 The results of that study investigating
escalated doses of hyperfractionated radiotherapy demonstrated a trend toward
increased overall survival and disease-free survival at 70.2 Gy. Although
neurologic improvement at 70.2 Gy was similar to that at 66.0 Gy (77% [30/39]),
survival times differed; the probability of survival at 2 years was only about
5% for children treated at 66.0 and 75.6 Gy and was 22% for children treated
at 70.2 Gy.
Similarly, 284 children with rhabdomyosarcoma were treated with hyperfractionated
EBRT to 59.4 Gy (5940 rad) at 1.1 Gy per fraction, twice daily with a 6- to
8-hour interfraction interval, to assess the toxicity of hyperfractionated
radiation combined with chemotherapeutic treatment.32
This was a 10% calculated dose increase of the biologically effective dose
over conventional daily fractionation. No deaths or unusual toxic effects
were reported in any of the patients treated (0% [0/284]).
Thirty-nine patients with Ewing sarcoma were treated by several different
regimens incorporating hyperfractionated EBRT at 1.2 Gy per fraction, twice
daily with a 6-hour interfraction interval.33
Total dose delivered depended on response to chemotherapy and was 50.4 Gy
(5040 rad) for complete regression, 55.2 Gy (5520 rad) for 50% resolution,
and 60 Gy (6000 rad) for 50% resolution of soft tissue mass. The 5-year local
control rate for the 3 different systemic regimens and the hyperfractionated
radiosurgery as given in this paragraph was similar at 88% to 92%, indicating
improved long-term function as compared with once-a-day standard treatment
regimens.
Hyperfractionated EBRT and adjuvant chemotherapy has been used to treat
23 children with medulloblastoma and primitive neuroectodermal tumors.29 Both the primary site and neuroaxis were treated
with 1.0-Gy (100-rad) fractions, twice daily with 4- to 6-hour interfraction
intervals. Total dose to the primary tumor and other areas of measurable intracranial
disease was 72 Gy (7200 rad). The prophylactic craniospinal dose was 36 Gy
(3600 rad), with boosting to metastatic spinal deposits. After radiation treatment,
all patients had multiagent chemotherapy. Of 15 patients with high T stages
with large locally invasive tumor and no evidence of metastases, 14 were in
continuous remission for a median of 78 months. No patient in this group died.
Of 4 patients with both high T and M stages, 2 were alive in continuous remission
at 69 and 35 months, and 2 died at 18 and 30 months. In 4 patients whose primary
site was outside of the cerebellum, 3 of whom had M3 disease, none responded
completely to therapy.
The increased efficacy and minimal toxicity demonstrated in these clinical
studies and in our laboratory evaluations with the use of hyperfractionated
EBRT suggest a possible application in the treatment of pediatric retinoblastoma.
The present study documents that the TCD50 for 2.0-Gy EBRT,
once daily, was 45.0 Gy in this transgenic murine model of retinoblastoma.
In contrast, with the use of 1.2-Gy fractions administered twice per day,
a TCD50 of 33.0 Gy (3300 rad) was observed, demonstrating the increased
efficacy of hyperfractionated EBRT.
Previous experiments in our laboratory have documented the TCD50s and dose-effect curves for transgenic mice treated with clinically
relevant EBRT doses.42-43 The
current study further establishes a clear dose-effect relationship of EBRT
delivered in hyperfractionation. These results suggest that lowering the fraction
per radiation dose from the conventional 1.8 to 2.0 Gy once per day to a fractionated
dose of 1.2 Gy twice per day may provide enhanced tumor control, while reducing
the overall treatment dose.
In the past 10 years, systemic chemotherapy has largely replaced EBRT
in the treatment of medium to large tumors (Reese-Ellsworth stage IV and V).9 Systemic administration of chemotherapy, as a primary
treatment modality, has been used in small to medium-sized tumors to decrease
the tumor volume of intraocular retinoblastoma.44-49
Clinical trials have also demonstrated the benefits of chemoreduction combined
with adjuvant therapy.46, 50-52
Although effective in reducing the tumor volume in small to medium-sized tumors,
chemoreduction plus local cryotherapy, laser photocoagulation, thermotherapy,
or plaque radiation therapy has not proved as effective in the treatment of
large tumors (Reese-Ellsworth group 5).48, 53
Recent studies indicate that EBRT is often needed as salvage therapy after
failure of systemic chemoreduction management of large retinoblastoma tumors.48, 53 In addition, new reports of patients
treated with EBRT indicate lower incidences of second tumor development among
long-term survivors of heritable retinoblastoma than previously reported.5, 54 External beam radiation therapy remains
a valuable treatment option, particularly in the management of tumors with
extensive vitreous seeding, for tumors located near the optic nerve, or after
the failure of systemic chemotherapy.
Hyperfractionated radiotherapy may prove most useful in combination
with adjuvant therapies, or as salvage therapy for patients who have previously
undergone systemic chemotherapy. To decrease the risk of secondary malignancy
after chemotherapy treatment, new studies have investigated the local delivery
of chemotherapy via subconjunctival injection, peribulbar injection, episcleral
balloon delivery, and coulomb-controlled iontophoresis.42-43,55-58
The use of hyperfractionated EBRT in combination with local chemotherapy may
provide effective treatment, while minimizing toxicity and the increased incidence
of secondary malignancy.
This study demonstrates improved efficacy of twice vs once-daily radiotherapy
without increased toxicity in short-term follow-up within a transgenic murine
model of heritable retinoblastoma. Limitations of this study are inherent
in the application of animal modeling to human clinical disease. These data
establish a framework for pilot clinical evaluation of hyperfractionation
in the treatment of childhood retinoblastoma requiring EBRT. Hyperfractionated
radiotherapy may offer the benefits of increased tumor control in patients
with childhood retinoblastoma, while minimizing the total radiation dose and
thus potentially lowering the risk of treatment-related complications.
AUTHOR INFORMATION
Submitted for publication July 25, 2000; final revision received July
23, 2001; accepted August 16, 2001.
This study was supported by Fight for Sight and Research to Prevent
Blindness, New York, NY; Miami Veterans Affairs Medical Center, University
of Miami; and the American Cancer Society Florida Division, Tampa.
We thank Rick Fitterer, RTT, Tony Iacavone, RTT, Gino Giordani, RTT,
and Cathy Boehm, RTT, for technical assistance with EBRT.
Corresponding author and reprints: Timothy G. Murray, MD, Bascom
Palmer Eye Institute, PO Box 016880, Miami, FL 33101.
From the Bascom Palmer Eye Institute, Department of Ophthalmology (Mss
Hayden and Cicciarelli, Drs Murray, Scott, Alexandridou, and Markoe, and Messrs
Hernandez and Feuer), and Department of Radiation/Oncology, Sylvester Comprehensive
Cancer Center (Drs Murray, Wu, and Markoe), University of Miami, Miami, Fla;
and Department of Ophthalmology, University of California, San Francisco (Ms
Fulton and Dr O'Brien).
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