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Factors Predictive of Recurrence of Retinal Tumors, Vitreous Seeds, and Subretinal Seeds Following Chemoreduction for Retinoblastoma
Carol L. Shields, MD;
Santosh G. Honavar, MD;
Jerry A. Shields, MD;
Hakan Demirci, MD;
Anna T. Meadows, MD;
Thomas John Naduvilath, MSc
Arch Ophthalmol. 2002;120:460-464.
ABSTRACT
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Objective To identify the clinical features of eyes with retinoblastomas that
predict the recurrence of retinal tumors, vitreous seeds, and subretinal seeds
following treatment with chemoreduction.
Design Prospective nonrandomized single-center clinical trial.
Setting Ocular oncology service at Wills Eye Hospital of Thomas Jefferson University
(Philadelphia, Pa) in conjunction with the division of oncology at Children's
Hospital of Philadelphia.
Participants There were 158 eyes with 364 tumors in 103 consecutive patients with
retinoblastoma managed with chemoreduction between June 1994 and August 1999.
Intervention All patients received treatment for retinoblastoma with 6 cycles of
chemoreduction using vincristine, etoposide, and carboplatin combined with
focal treatment (cryotherapy, thermotherapy, or plaque radiotherapy) for each
retinal tumor.
Main Outcome Measures The 3 main outcome measures included recurrence of retinal tumors, recurrence
of vitreous seeds, and recurrence of subretinal seeds. The clinical features
at the initial examination were analyzed for their association with the main
outcome measures using a series of Cox proportional hazards regressions.
Results All retinal tumors, vitreous seeds, and subretinal seeds showed an initial
favorable response of regression during this treatment regimen. Using Kaplan-Meier
estimates, at least 1 retinal tumor recurrence per eye was found in 37% of
eyes at 1 year, 51% at 3 years, and no further increase at 5 years. By multivariate
analysis, the only factor predictive of retinal tumor recurrence was the presence
of tumor-associated subretinal seeds at the initial examination. Of the 54
eyes that had vitreous seeds at the initial examination, vitreous seed recurrence
was found in 26% of eyes at 1 year, 46% at 3 years, and 50% at 5 years. By
univariate analysis, the only factor predictive of vitreous seed recurrence
was the presence of tumor-associated subretinal seeds at the initial examination.
Of the 71 eyes that had subretinal seeds at the initial examination, subretinal
seed recurrence was detected in 53% of eyes at 1 year, 62% at 3 years, and
no further increase at 5 years. By multivariate analysis, factors predictive
of subretinal seed recurrence included a tumor base greater than 15 mm and
a patient age of 12 months or younger at diagnosis. There were no patients
who developed retinoblastoma metastasis, pinealoblastoma, or second malignant
neoplasms.
Conclusions Chemoreduction combined with focal therapy is effective for selected
eyes with retinoblastomas. Eyes with subretinal seeds at initial examination
are at particular risk for recurrence of retinal tumor and vitreous seeds.
Younger patients with large tumors are at risk for recurrence of subretinal
seeds. Retinal tumor and subretinal seed recurrence seems to manifest within
3 years of follow-up. Close follow-up of all patients treated with chemoreduction
is warranted.
INTRODUCTION
CHEMOREDUCTION has become an important method in the management of retinoblastoma.1-13
This technique has been employed in an effort to avoid enucleation and external
beam radiotherapy for children with retinoblastoma, especially those with
bilateral disease. Chemoreduction involves the use of intravenous chemotherapy
coupled with focal treatments to induce complete regression of the tumor.
Management of this disease involves attention to 3 anatomic sites of tumor,
including the individual retinal tumor(s), associated vitreous tumor (termed
"vitreous seeds"), and associated subretinal tumor (termed "subretinal seeds").
Retinal tumors generally respond rapidly to chemoreduction; then, subsequent
consolidation with focal methods, such as cryotherapy, thermotherapy, or plaque
radiotherapy, is employed. Eyes with additional vitreous seeds or subretinal
seeds are managed differently using chemoreduction without focal consolidation
treatments because the number of seeds is usually far beyond the capability
of focal treatment methods and the multitude of tiny seeds typically respond
with regression, calcification, and often complete disappearance after several
months of treatment.
Prior statistical studies regarding chemoreduction for retinoblastoma
have focused on the factors related to treatment failure and the need for
external beam radiotherapy or enucleation.13
This information is important for the clinician in determining whether chemoreduction
would be useful for a child with retinoblastoma. In this analysis, we specifically
address the 3 anatomic sites of retinoblastoma, including individual retinal
tumors, vitreous seeds, and subretinal seeds. We evaluated the effect of chemoreduction
in controlling tumors at each of these 3 sites. This information may be useful
for the retinoblastoma specialist in anticipating recurrence and providing
a window of time to expect each event.
PATIENTS AND METHODS
All new patients with retinoblastoma who were treated initially with
chemoreduction (Table 1) at the
ocular oncology service, Wills Eye Hospital, Thomas Jefferson University (Philadelphia,
Pa) in conjunction with the division of oncology at Children's Hospital of
Philadelphia were enrolled for this prospective clinical trial. The eligibility
criteria for inclusion have been detailed in previous reports and include
children with intraocular retinoblastomas in whom the involved eye of the
unilaterally affected patient or either eye of the bilaterally affected patient
would ordinarily require enucleation or external beam radiotherapy to cure
the disease, based on published indications.1-3,9
Any patient whose tumor(s) could be properly controlled with conservative
methods alone (cryotherapy, laser photocoagulation, thermotherapy, plaque
radiotherapy) were not eligible for inclusion in the chemotherapy protocol
unless the opposite eye had features that required chemotherapy.1-2
Exclusion criteria for treatment with chemoreduction included biomicroscopic
evidence of iris neovascularization; neovascular glaucoma; tumor invasion
into the anterior chamber, iris, optic nerve, choroid, or extraocular tissues
as documented by clinical, ultrasonographic, and neuroimaging modalities;
or any eye in which globe prognosis was judged poor. Systemic exclusion criteria
were evidence of systemic metastasis, prior chemotherapy, prior treatment
for retinoblastoma, or inadequate renal, hepatic, or auditory function. The
potential risks and benefits of the chemoreduction protocols were discussed
with the patients' parents or guardians and informed consent was signed. The
chemotherapeutic agents employed in the protocols included intravenous vincristine,
etoposide, and carboplatin as presented in Table 1. The duration of treatment was 6 cycles per protocol (Children's
Hospital of Philadelphia 582). The protocol was approved by the Children's
Hospital of Philadelphia Committee for the Protection of Human Subjects.
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Table 1. Chemoreduction Regimen and Doses for Intraocular Retinoblastoma
(6 Cycles)
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All data were collected in a prospective fashion. Each retinoblastoma
was measured for greatest basal dimension (in millimeters) using the indirect
ophthalmoscope, and thickness (in millimeters) measured by A-scan and B-scan
ultrasonography and indirect ophthalmoscopy. The proximity of the nearest
tumor margin to the optic disc and foveola was recorded. The presence and
extent of subretinal fluid and the presence and extent of tumor seeding in
the vitreous and subretinal space were recorded.
Ocular oncologic follow-up was provided, with examination under anesthesia
on a monthly basis after initiation of chemoreduction until control of the
disease was achieved. Thereafter, examinations were provided every 2 to 4
months as needed. At each examination, the individual retinal tumors were
measured in base and thickness. The status of the vitreous seeds, subretinal
seeds, and subretinal fluid was noted. When maximum retinal tumor regression
was achieved, usually at cycle 2 or 3, focal treatment using thermotherapy
or cryotherapy coupled with chemoreduction9, 11
was applied to all retinal tumors. Recurrent retinal tumors, vitreous seeds,
and subretinal seeds were identified on follow-up and treated with methods
including cryotherapy, thermotherapy, laser photocoagulation, and plaque radiotherapy
to avoid external beam radiotherapy and enucleation. The focal treatment selected
for each recurrent tumor or seed depended on several factors, including the
tumor or seed location, status of the opposite eye, visual acuity in the involved
eye and opposite eye, and, most importantly, tumor or seed size.
The clinical data were analyzed with regard to 3 main outcome measures:
recurrence of retinal tumors, recurrence of vitreous seeds, and recurrence
of subretinal seeds. The effect of each clinical variable recorded at the
time of initial examination at the ocular oncology service on the development
of these outcomes was analyzed by a series of univariate Cox proportional
hazards regressions. The correlation among the variables was determined by
Pearson correlations. All variables were analyzed as discrete variables. Variables
that were continuous were analyzed by grouping them into discrete categories.
The variables that were significant on a univariate level (P .05, Fisher exact and  2 tests) were entered into
the multivariate Cox regression analysis using the enter method. For variables
that showed a high degree of correlation, only 1 from the set of associated
variables was entered at a time into subsequent multivariate models. A final
multivariate model fitted variables that were identified as significant predictors
(P.05, Wald statistic or 95% confidence interval
of the relative risk) from the initial model as well as variables deemed clinically
important for the outcomes of retinal tumor recurrence, vitreous seed recurrence,
and subretinal seed recurrence. In the final model, a predictor was considered
to be a significant risk factor if the 95% confidence interval of its relative
risk did not contain a risk value of 1.0.
RESULTS
There were 364 retinoblastomas in 158 eyes of 103 patients enrolled
in the chemoreduction protocol. The patients received chemoreduction, as presented
in Table 1, for a mean of 6 cycles
(median, 6 cycles; range, 2-6 cycles). The reasons for employing fewer than
6 cycles included poor tumor response in 19 cases, patient or family compliance
difficulties in 7 cases, and family preference owing to excellent control
in 3 cases. The mean follow-up was 29 months (median, 28 months; range, 2-63
months). Some of the patients in this study were included in previously published
studies.8-9,13 The
demographic findings of this group and chemoreduction protocol have been outlined
in a previous publication.13 The Reese-Ellsworth
stage of each eye included group I in 9 (6%), group II in 26 (16%), group
III in 16 (10%), group IV in 32 (20%), and group V in 75 (48%) eyes. The following
results of the initial visit describe the 3 anatomic sites of tumors, including
retinal tumor, vitreous seeds, and subretinal seeds. Overall, there was a
mean of 2 retinal tumors per eye (median, 2 tumors; range, 1-10 tumors). Of
the largest tumor in each eye, the mean retinal tumor base was 13 mm (median,
14 mm; range, 1-24 mm); mean tumor thickness was 7 mm (median, 7 mm; range,
1-20 mm); mean tumor distance to the optic disc was 2 mm (median, 0 mm; range,
0-20 mm); and mean tumor distance to the foveola was 2 mm (median, 0 mm; range,
0-22 mm). At the initial visit, retinoblastoma was visible in the vitreous
as vitreous seeds in 54 eyes (34%) and retinoblastoma was visible in the subretinal
space as subretinal seeds in 71 eyes (45%). Vitreous seeding involved a mean
of 5 clock hours (median, 3 clock hours; range, 1-12 clock hours). The vitreous
seeds were local in 32 eyes (60%) and diffuse in 22 eyes (40%). Subretinal
seeding involved a mean of 5 clock hours (median, 5 clock hours; range, 1-12
clock hours). The subretinal seeds were mainly in the posterior pole in 12
eyes (17%), at the equator in 21 (30%), at the ora serrata in 30 (42%), and
diffusely located in 8 (11%). Subretinal seeds were primarily located inferiorly
in 51 eyes (72%), temporally in 1 (1%), superiorly in 2 (3%), nasally in 3
(4%), in the macula in 6 (8%), and diffusely in 8 (12%). Subretinal fluid
was present in 95 eyes (60%), involved a mean of 60% of the retina (median,
70%), and extended for a mean of 9 clock hours (median, 11 clock hours; range,
1-12 clock hours).
Retinal tumor recurrence of at least 1 tumor was found in 69 (44%) of
158 eyes. Using Kaplan-Meier estimates, at least 1 retinal tumor recurrence
was found in 37% of eyes at 1 year, 51% at 3 years, and 51% at 5 years (Table 2). Univariate and multivariate risk
factors for retinal tumor recurrence are presented in Table 3. The mean time interval from chemoreduction initiation to
first retinal tumor recurrence (per eye) was 10 months (median, 9 months;
range, 2-27 months) and mean time interval to last retinal tumor recurrence
(per eye) was 13 months (median, 11 months; range, 4-48 months). Focal treatment
of the recurrent retinal tumor included cryotherapy for 33 tumors, thermotherapy
for 31 tumors, and plaque radiotherapy for 22 tumors. External beam radiotherapy
was required in 14 eyes and enucleation in 19 eyes. Some tumors received more
than 1 treatment method and some eyes received more than 1 treatment method.
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Table 2. Chemoreduction* for Retinoblastoma in 102 Consecutive Patients
(158 Eyes): Overview of Recurrence of Retinal Tumor, Vitreous Seeds, and Subretinal
Seeds
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Table 3. Chemoreduction* for Retinoblastoma in 103 Consecutive Patients
(158 Eyes): Univariate and Multivariate Analysis of Clinical Factors Predictive
of Retinal Tumor Recurrence
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Of the 54 eyes with vitreous seeds on initial examination, recurrence
of at least 1 vitreous seed was noted in 21 (39%). Using Kaplan-Meier estimates,
vitreous seed recurrence was found in 26% of eyes at 1 year, 46% at 3 years,
and 50% at 5 years (Table 2).
Univariate and multivariate risk factors for vitreous seed recurrence are
presented in Table 4. The mean
interval from chemoreduction initiation to first vitreous seed recurrence
(per eye) was 14 months (median, 12 months; range, 3-37 months) and mean interval
to last vitreous seed recurrence (per eye) was 21 months (median, 18 months;
range, 6-50 months). The mean number of recurrent vitreous seed sites was
3 (median, 3; range, 1-8 sites). Recurrent vitreous seeds involved a mean
of 6 clock hours of the fundus (median, 6 clock hours; range, 1-12 clock hours).
Treatment of vitreous seed recurrence included plaque radiotherapy for 3 eyes,
external beam radiotherapy for 11 eyes, and enucleation for 16 eyes. Some
eyes received more than 1 treatment method.
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Table 4. Chemoreduction* for Retinoblastoma in 103 Consecutive Patients
(158 Eyes): Univariate and Multivariate Analysis of Clinical Factors Predictive
of Vitreous Seed Recurrence
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Of the 71 eyes with subretinal seeds on initial examination, at least
1 subretinal seed recurrence was detected in 40 (56%). Using Kaplan-Meier
estimates, subretinal seed recurrence was found in 53% of eyes at 1 year,
62% at 3 years, and 62% at 5 years (Table
2). Univariate and multivariate risk factors for subretinal seed
recurrence are presented in Table 5.
The mean interval from chemoreduction initiation to first subretinal seed
recurrence (per eye) was 8 months (median, 6 months; range, 1-33 months) and
time interval to last subretinal seed recurrence (per eye) was 16 months (median,
15 months; range, 5-50 months). The mean number of recurrent subretinal seed
sites was 4 (median, 3; range, 1-13 sites). Recurrent subretinal seeds extended
for a mean of 6 clock hours (median, 6 clock hours; range, 1-12 clock hours).
The recurrent seeds were found in sites of previous serous retinal detachment
in 38 eyes (95%). The recurrent subretinal seeds were located anteroposteriorly
mainly at the ora serrata in 20 eyes (51%), equator in 14 (35%), macula in
3 (7%), and diffuse at all regions in 3 (7%). The main quadrant location included
inferior quadrant in 28 eyes (70%), temporal in 0 (0%), superior in 1 (2%),
nasal in 5 (12%), macula in 3 (7%), and diffuse in 3 (8%). Treatment of the
subretinal seed recurrences included cryotherapy in 45 eyes, thermotherapy
in 19, plaque radiotherapy in 22, external beam radiotherapy in 13, and enucleation
in 23. Most eyes received more than 1 treatment method for multifocal recurrences.
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Table 5. Chemoreduction* for Retinoblastoma in 103 Consecutive Patients
(158 Eyes): Univariate and Multivariate Analysis of Clinical Factor Predictive
of Subretinal Seed Recurrence
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No patient developed metastatic retinoblastoma or serious adverse effects
of the chemotherapy, such as renal adverse effects, hearing loss, or second
cancers. Pinealoblastoma and intracranial neuroblastic malignancy did not
occur in any case.
COMMENT
Chemoreduction has assumed a major role in the management of retinoblastoma.13 Preliminary observations have documented dramatic
regression of retinoblastoma following chemoreduction and these findings have
generated enthusiasm for this treatment modality. Approximately 50% of affected
eyes treated with chemoreduction are successfully preserved with avoidance
of external beam radiotherapy or enucleation.13
The rate of globe preservation is best with less advanced eyes (85%), such
as those in Reese-Ellsworth groups I to IV whereas with more advanced eyes,
such as those in Reese Ellsworth group V, preservation is less successful
at 47%.13 To reach this goal, the involved
eye(s) requires tedious monitoring and possibly extensive treatment using
focal measures, such as cryotherapy, thermotherapy, or plaque radiotherapy,
to avoid ultimate failure.
The main concern with chemoreduction is the lack of stable tumor control
following treatment. Recurrence of retinoblastoma is generally classified
according to 1 of 3 anatomic sites, including tumors in the retina, vitreous,
or subretinal space. This anatomic classification of tumor is important since
recurrence varies in appearance, course, and management depending on its site.
Additionally, eyes can have recurrence at more than 1 site. In this analysis,
we found recurrence of at least 1 retinal tumor in 51% of eyes at 3 years'
follow-up and no change in this percentage at 5 years' follow-up (Table 2). Those at greatest risk for retinal
tumor recurrence were eyes with tumor-associated subretinal seeds surrounding
the base of the tumor (Table 3).
It is unclear how this factor might lead to intraretinal recurrence, but it
might reflect the discohesive nature of the tumor and perhaps inadequate accessibility
of the less vascular portions of the retinal mass to chemotherapy. In some
instances it is difficult to differentiate between recurrent intraretinal
tumor and recurrent subretinal seeds immediately adjacent to the tumor. With
this in mind, perhaps some of the tumors that we judged to be recurrent were
actually recurrent subretinal seeds at the retinal tumor site.
At 5 years' follow-up, vitreous seed recurrence was found in 50% of
eyes and subretinal seed recurrence in 62% of eyes (Table 2). Patients at greatest risk for vitreous or subretinal seed
recurrence were those who, at initial examination, were younger, had large
tumor dimensions, and had tumor-associated subretinal seeds (Table 4 and Table 5).
It is evident that eyes with subretinal seeds at initial examination are particularly
at risk for future recurrence of retinal tumor and vitreous or subretinal
seeds and should be carefully followed up. It is unclear how the presence
of initial subretinal seeds is a risk factor for the eventual development
of recurrent vitreous seeds. We doubt that subretinal seeds directly transgress
the retina into the vitreous. On the other hand, we suspect that subretinal
seeds might signify a more discohesive tumor, one that also might have macroscopic
or microscopic vitreous seeds at initial examination and are at risk for recurrence.
Vitreous and subretinal seed recurrence can ultimately lead to advanced tumor
and loss of the eye. Thus, vitreous and subretinal seeds should be carefully
documented and followed up closely. If recurrence is detected, prompt treatment
is advised. Tedious fundus examination, with knowledge of the appearance of
seed recurrence, is critical since seeds are often only 50 to 100 µm
at the time recurrence is detected. All children receiving a chemoreduction
protocol should be monitored by a retinoblastoma specialist who is able to
detect minute recurrences and capable of treating the recurrences.
Recurrence is especially notable after chemoreduction is discontinued.
In this study, the mean interval from discontinuation of chemoreduction to
first recurrence of retinal tumor was 4 months, recurrence of vitreous seeds
was 2 months, and recurrence of subretinal seeds was 2 months. Thus, monitoring
of the eye is important during chemoreduction for applying focal treatments
but is especially critical following chemoreduction to detect recurrence.
It is reassuring to know that most children manifest their recurrent retinal
tumors and subretinal seeds by 3 years after treatment with little recurrence
thereafter; accordingly, follow-up can be adjusted for this time interval.
Vitreous seed recurrence, however, continues to be a problem up to 5 years
after treatment and potentially longer; therefore, patients with vitreous
seeds at initial examination might require cautious ocular examination for
many years following treatment.
Recurrence of vitreous seeds or subretinal seeds may not necessarily
reflect resistance of the tumor seeds to chemotherapy. This may, on the other
hand, represent inadequate penetration of the chemotherapy to relatively avascular
sites in the vitreous cavity and subretinal space. Wilson et al14
demonstrated in rabbits that the application of cryotherapy to the sclera
prior to intravenous delivery of carboplatin resulted in increased penetration
of carboplatin into the vitreous. It is believed that any modality that disturbs
the blood-retinal barrier can bring about a similar phenomenon. Thus, thermotherapy
may also increase the vitreous penetration of carboplatin. Based on this,
we generally apply cryotherapy at the time of institution of chemoreduction
in all eyes, and at each subsequent cycle, cryotherapy or thermotherapy is
applied to the tumors for consolidation, secondarily permitting exudation
of the carboplatin into the vitreous cavity. Penetration of carboplatin in
the subretinal space is more difficult to measure and maintain.15
There are limitations in this report. First, our group represents patients
from a tertiary referral center and we may treat more advanced cases in a
heroic attempt to save a remaining eye. Second, we acknowledge that some of
the eyes classified as retinal tumor recurrences may have been subretinal
seed recurrences adjacent to the tumors, but the clinical differentiation
is challenging. Third, we employed a set protocol of chemoreduction for a
set duration. There may be other chemoreduction protocols that might better
control retinoblastomas. Fourth, with longer follow-up, we might detect more
recurrence. However, in this comprehensive statistical analysis, important
clinical information is evident to guide the ocular oncologist and pediatric
oncologist in the management of affected patients and to assist in anticipating
recurrence. Based on this report, we are presently treating advanced disease
with more aggressive regimens for longer durations.
In summary, chemoreduction and focal conservative treatment for retinoblastoma
is effective, but recurrence of at least 1 retinal tumor per eye, vitreous
seeds, and subretinal seeds is found in 51%, 50%, and 62% of eyes, respectively,
at 5 years' follow-up. Eyes with vitreous or subretinal seeds at initial examination
can have hundreds or thousands of seeds initially. The recurrence of 1 or
2 seeds or even a group of seeds does not indicate failure of this modality
since it represents only a minor degree of seeding that was manifested at
the initial visit. However, the need for meticulous fundus examination of
these children during and after chemoreduction is underscored. Numerous focal
treatments may be necessary to adequately control the recurrences and ultimately
preserve the globe and, most importantly, the patient's life.
AUTHOR INFORMATION
Submitted for publication September 4, 2001; final revision received
September 25, 2001; accepted December 13, 2001.
This study was supported by the Paul Kayser International Award of Merit
in Retina Research, Houston, Tex (Dr J. A. Shields); the Macula Foundation,
New York, NY (Dr C. L. Shields); the Eye Tumor Research Foundation, Philadelphia
(Dr C. L. Shields); Orbis International, New York (Dr Honavar); and the Hyderabad
Eye Research Foundation, Hyderabad, India (Dr Honavar).
Corresponding author and reprints: Carol L. Shields, MD, Ocular Oncology
Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107.
From the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson
University, (Drs C. L. Shields, Honavar, J. A. Shields, and Demirci); the
Division of Oncology, The Children's Hospital of Philadelphia, (Dr Meadows),
Philadelphia, Pa; and the Ocular Oncology Service, LV Prasad Eye Institute,
Hyderabad, India (Dr Honavar and Mr Naduvilath).
REFERENCES
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