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Postenucleation Adjuvant Therapy in High-Risk Retinoblastoma
Santosh G. Honavar, MD;
Arun D. Singh, MD;
Carol L. Shields, MD;
Anna T. Meadows, MD;
Hakan Demirci, MD;
Jacqueline Cater, PhD;
Jerry A. Shields, MD
Arch Ophthalmol. 2002;120:923-931.
ABSTRACT
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Purpose The main purpose of this study was to determine the efficacy of postenucleation
adjuvant therapy in preventing metastasis in cases of high-risk retinoblastoma.
Methods This was a retrospective, nonrandomized comparative study. Of 1020 consecutive
patients with retinoblastoma had were managed at a referral center between
January 1974 and December 1999, 80 (8%) of those analyzed had unilateral sporadic
cases that were treated by primary enucleation and that had high-risk characteristics
for metastasis on histopathology reports (anterior chamber seeding, iris infiltration,
ciliary body infiltration, massive choroidal infiltration, invasion of optic
nerve lamina cribrosa, retrolaminar optic nerve invasion, invasion of optic
nerve transection, scleral infiltration, and extrascleral extension). The
main outcome measure was the development of metastasis at a minimum follow-up
period of 12 months.
Results There were 44 male and 36 female patients, with age ranging from 1 day
to 16 years (median, 33 months). A single histopathologic high-risk characteristic
was present in 50 patients (62.5%). Thirty patients (37.5%) manifested 2 or
more high-risk characteristics. Forty-six patients (58%) had received postenucleation
adjuvant therapy (chemotherapy with or without orbital external beam radiotherapy).
Adjuvant therapy was not administered in 34 patients (42%). Metastasis occurred
in 10 patients (13%) at a median of 9 months (range, 6-57 months) following
enucleation. Eight (80%) of those who developed metastasis had not received
adjuvant therapy. A significant difference (P = .02)
was found in the incidence of metastasis between the group that had received
adjuvant therapy (4%; 2/46) and the group that had not (24%; 8/34). The beneficial
effect of adjuvant therapy was statistically significant in subgroups of patients
with massive choroidal infiltration (P = .04) or
retrolaminar optic nerve invasion (P = .04). There
were no adjuvant therapy–related serious systemic complications.
Conclusion Postenucleation adjuvant therapy is safe and effective in significantly
reducing the occurrence of metastasis in patients with retinoblastoma manifesting
histopathologic high-risk characteristics.
INTRODUCTION
THE PROGNOSIS of retinoblastoma has improved remarkably during the last
century.1-5
It has evolved from an almost uniformly fatal malignant neoplasm to one that
is cured in more than 90% of cases in medically advanced countries.1-5
The improved prognosis is believed to be due to earlier diagnosis and better
methods of management.1-3
The major causes of mortality in patients with retinoblastoma include second
malignant neoplasm, pinealoblastoma, and metastasis.6-8
Second malignant neoplasia and pinealoblastoma develop almost exclusively
in heritable cases, whereas metastasis contributes significantly to tumor-related
mortality in both heritable and nonheritable retinoblastoma.6-8
Metastatic retinoblastoma is reported to develop in less than 10% of
patients in advanced countries.1-5
However, it is a major contributor to retinoblastoma-related mortality in
developing nations.6, 9 It may
be possible to reduce the risk of metastatic retinoblastoma by providing postenucleation
adjuvant therapy to selected patients.2, 6
Adjuvant therapy may include systemic chemotherapy and orbital external beam
radiotherapy.
With improved understanding of the risk factors predictive of metastasis,11-17
and the availability of effective chemotherapy regimens for intraocular retinoblastoma,18-20 it would seem logical
to consider adjuvant chemotherapy following enucleation to prevent metastasis
in high-risk cases. Nevertheless, the utility of adjuvant chemotherapy in
such cases remains debatable, and its role has yet to be clearly defined.21-34
Adjuvant orbital external beam radiotherapy following enucleation is recommended
in patients with tumor invasion of optic nerve transection, scleral and extrascleral
extension, spontaneous or accidental ocular perforation, and intraocular surgery
for unrecognized retinoblastoma.6, 35
The role of such therapy, however, is not well established. The controversy
regarding adjuvant therapy is compounded by disagreement over the histopathologic
prognostic factors that define "high-risk" for developing metastasis.12-17
The overall rarity of retinoblastoma, and the even more unusual finding of
extraretinal involvement, have limited the experience with adjuvant therapy.
In this retrospective comparative study, we have examined the role of adjuvant
therapy in preventing metastasis in a well-defined subset of patients with
unilateral retinoblastoma managed by primary enucleation, who histopathologic
high-risk characteristics.
METHODS
This was a retrospective, nonrandomized study with a concurrent comparison
group. The computerized patient database at the Oncology Service of Wills
Eye Hospital (Philadelphia, Pa) was searched for patients with retinoblastoma.
Of 1020 consecutive patients with retinoblastoma managed between January 1974
and December 1999, 630 had undergone enucleation. The medical records of these
patients were reviewed for laterality of retinoblastoma, treatment modalities,
and histopathologic features of the enucleated eye. Eighty patients (8%) with
unilateral sporadic retinoblastoma who had undergone primary enucleation and
had predefined specific high-risk characteristics on histopathology reports
were identified for inclusion in this study (Table 1).
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Table 1. Role of Postenucleation Adjuvant Therapy in Preventing Metastasis
in High-Risk Retinoblastoma: Inclusion Criteria
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The patient data were reviewed for demographic information, clinical
findings and management, and histopathologic features. The data collected
included the date of diagnosis, age at diagnosis (months), sex (male, female),
race (African American, white, Hispanic, Asian), hereditary pattern (familial,
sporadic), laterality (unilateral, bilateral), the eye involved (right, left),
and prior treatment or intraocular surgery. The clinical information included
intraocular pressure, presence of macroscopic anterior chamber seeding, and
neovascularization of the iris. Reese-Ellsworth staging of retinoblastoma10 were noted for each patient. Histopathology reports
were reviewed for the presence of specific features (Table 1). Details of systemic evaluation (computed tomographic scan,
magnetic resonance imaging, bone marrow examination, cerebrospinal fluid cytology)
were recorded. Details of postenucleation adjuvant therapy (chemotherapy,
orbital external beam radiotherapy) were noted. In patients who received adjuvant
chemotherapy, the drug regimen, duration, and systemic complications (as periodically
assessed by a pediatric oncologist) were noted. In those who received adjuvant
orbital external beam radiotherapy, the total dose and fractionation schedule
were recorded. If adjuvant therapy was not administered, the reason governing
the decision was elicited. Information regarding the outcome included occurrence
of metastasis, date of detection of metastasis, interval between enucleation
and detection of metastasis (months), and the site of metastasis. The final
patient outcome (alive without metastasis, alive with metastasis, alive with
second malignant neoplasm, dead with metastasis, dead with second malignant
neoplasm, or dead because of other causes), the date of last follow-up, and
the duration of follow-up were noted.
The main interest of the statistical analysis was to assess the effect
of adjuvant therapy in preventing metastasis. The comparison was between the
group that received adjuvant therapy and the group that did not. In this nonrandomized
retrospective study, we first tested for comparability of the 2 groups and
the presence of potential confounding variables that interacted with adjuvant
therapy. A t test was used for continuous variables
and the Fisher exact test for discrete variables. We also tested the comparability
of the 2 groups that received different chemotherapy regimens. The influence
of adjuvant therapy in preventing metastasis in the presence of every individual
(and various logical) combination of histopathologic risk factor was analyzed
with the Fisher exact test. The proportion of patients free of metastasis
was calculated using the Kaplan-Meier method. The date of enucleation was
the starting point for the survival curve, and the detection of metastasis
was the end point. The adjuvant therapy was examined for its relationship
with the development of metastasis over time using the univariate Cox proportional
hazards regression model.
RESULTS
Our series consisted of the cases of 80 patients with unilateral sporadic
retinoblastomas who had undergone primary enucleation and had specific high-risk
characteristics on histopathology report (Table 1). There were 44 male (55%) and 36 female (45%) patients,
ranging in age from 1 day to 16 years (median, 33 months). Anterior chamber
tumor seeding was clinically detectable in 17 eyes (21%), and neovascularization
of iris was present in 30 eyes (38%). Retinoblastoma was clinically graded
Reese-Ellsworth stage IVb in 1 eye (1%), Va in 18 eyes (23%), and Vb in 61
eyes (76%). The systemic examination, bone marrow biopsy, and cerebrospinal
fluid cytology did not reveal the presence of metastasis in any of the patients
at the time of initial diagnosis of retinoblastoma. All of the patients underwent
enucleation 1 day to 2 weeks following the diagnosis of retinoblastoma. Fifty
patients (62.5%) had a single histopathologic risk factor, while 30 (37.5%)
had various combinations of multiple risk factors (2 risk factors in 20 patients,
3 risk factors in 9, and 5 risk factors in 1) (Figure 1, Figure 2, Figure 3, and Figure 4). Table 2 summarizes
the demographic, baseline clinical, and histopathologic features of the patients.
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Figure 1. Photomicrograph demonstrating
the massive choroidal infiltration of retinoblastoma (hematoxylin-eosin, original
magnification x100). Photomicrograph by Ralph C. Eagle, Jr, MD.
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Figure 2. Photomicrograph showing retrolaminar
optic nerve invasion by retinoblastoma (hematoxylin-eosin, original magnification
x50). Photomicrograph by Ralph C. Eagle, Jr, MD.
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Figure 3. Histopathological evidence of
the combined massive choroidal infiltration and invasion of the optic nerve
lamina cribrosa (hematoxylin-eosin, original magnification x100). Photomicrograph
by Ralph C. Eagle, Jr, MD.
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Figure 4. Photomicrograph demonstrating
the choroidal infiltration and extrascleral extension of retinoblastoma (hematoxylin-eosin,
original magnification x100). Photomicrograph by Ralph C. Eagle, Jr,
MD.
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Table 2. Demographic Characteristics, Clinical Features, and Histopathologic
Factors in 80 Patients With High-Risk Characteristics of Retinoblastoma*
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Adjuvant therapy was administered to 46 (58%) of 80 patients. The oncologist's
decision to withhold adjuvant therapy in 34 patients (42%) was based on the
then-prevailing protocols (for 29 patients) or parental choice (for 5 patients).
In the group that received adjuvant therapy, each of the 46 patients received
chemotherapy. The adjuvant chemotherapy regimen consisted of either a combination
of vincristine sulfate, doxorubicin hydrochloride, and cyclophosphamide (prior
to 1994), as in 21 patients (46%); or a combination of vincristine, etoposide,
and carboplatin (from 1994 onwards), as in 25 patients (54%) (Table 3). The baseline characteristics of the groups that received
2 different chemotherapy regimens were comparable. The duration of chemotherapy
ranged from 6 to 12 months (mean, 6.9 ± 1.4 months). Except for episodes
of reversible pancytopenia and infection in 11 patients (in 5 of 21 patients
who received the vincristine-doxorubicin-cyclophosphamide combination and
in 6 of 26 patients who received the vincristine-etoposide-carboplatin combination),
there were no permanent systemic complications of chemotherapy. Twelve patients
who had retrolaminar optic nerve invasion or invasion of optic nerve transection
had additionally received intrathecal chemotherapy (methotrexate, 6-12 mg).
Orbital external beam radiotherapy (4000-4500 rad [40-45 Gy]) was provided
to 14 patients with invasion of optic nerve transection, scleral infiltration,
or extrascleral extension. This was in addition to the chemotherapy that they
all received. No form of adjuvant therapy was provided to 34 (42%) of 80 patients.
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Table 3. Chemotherapy Regimens in 46 Patients of Retinoblastoma With
High-Risk Characteristics
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All of the patients were followed up for a minimum of 12 months after
enucleation. The median duration of follow-up was 59 months (range, 12-287
months). None of the patients developed a second malignant neoplasm in our
series. Systemic metastasis occurred in 10 patients (13%) at a median of 9
months (range, 6-57 months) following the diagnosis of retinoblastoma. The
sites of metastasis were the central nervous system in 3 patients, the skeletal
system in 1 patient, and the combined skeletal and central nervous systems
in 6 patients. Nine patients with metastasis died at a median of 15 months
(range, 1-30 months) following the detection of metastasis, while 1 patient
was alive in remission 16 months following detection of metastasis.
The rate of metastasis at the final follow-up visit was significantly
lower (Fisher exact test, P = .02) in the group that
received adjuvant therapy (2/46, 4%) compared with the group that did not
receive adjuvant therapy (8/34, 24%). Kaplan-Meier estimates showed that 96%
of patients who received adjuvant therapy would remain free of metastasis
at 10 years postenucleation compared with 76% of those who did not receive
adjuvant therapy (Cox proportional hazards regression analysis, P = .03; relative risk, 0.175; 95% confidence interval, 0.037-0.824)
(Figure 5).
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Figure 5. Kaplan-Meier estimates of the
proportion of patients free of metastasis in the group that received adjuvant
therapy (triangle line) and the group that did not (open circle line).
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Of the 2 patients who developed metastasis despite adjuvant therapy,
1 had retinoblastoma detected at birth, spontaneous corneal perforation, and
3 histopathologic high-risk characteristics (anterior chamber seeding, massive
choroidal infiltration, and extrascleral extension). This patient received
adjuvant chemotherapy and orbital external beam radiotherapy. The second patient
had ciliary body infiltration and retrolaminar optic nerve invasion and received
adjuvant chemotherapy. Metastasis was detected in these patients at 1 month
and 2 months, respectively, following completion of chemotherapy. Of the 8
patients who developed metastasis in the group that did not receive adjuvant
therapy, the histopathologic risk factors included anterior chamber seeding
in 1 patient, retrolaminar optic nerve invasion in 3, a combination of anterior
chamber seeding and massive choroidal infiltration in 1, massive choroidal
infiltration and invasion of optic nerve lamina cribrosa in 1, massive choroidal
infiltration and retrolaminar optic nerve invasion in 1, and massive choroidal
infiltration and scleral infiltration in 1.
Many of the possible effects, including the difference in efficacy of
2 chemotherapy regimens and the additional role of intrathecal chemotherapy
and orbital external beam radiotherapy, were statistically inestimable owing
to the small number of events (metastasis) in the study. The influence of
adjuvant therapy in preventing metastasis in each individual and the combination
of histopathologic risk factors were analyzed by the Fisher exact test (Table 4). The beneficial effect of adjuvant
therapy in preventing metastasis was statistically significant in patients
with retrolaminar optic nerve invasion (P = .02)
as the single histopathologic risk factor, and with massive choroidal infiltration
(P = .001) as one of the multiple risk factors. Both
these variables were again outstanding when all of the individual histopathologic
risk factors were analyzed, irrespective of whether they existed in isolation
or in combination (retrolaminar optic nerve invasion, P = .04; massive choroidal infiltration, P
= .04). Thirty-four patients had either retrolaminar optic nerve invasion
or invasion of optic nerve transection. Twenty-four of them received adjuvant
therapy, of whom only 1 (4%) developed systemic metastasis. Of the 10 patients
who did not receive adjuvant chemotherapy, 4 (40%) developed systemic metastasis.
This difference was statistically significant (P
= .02). Twelve patients had either a combination of massive choroidal infiltration
and retrolaminar optic nerve invasion, or optic nerve invasion to transection.
None of the 10 who received adjuvant therapy developed metastasis, while 1
of the 2 who did not receive adjuvant therapy developed metastasis. The difference,
however, was not statistically significant (P = .17).
The subgroup of patients with massive choroidal infiltration, retrolaminar
optic nerve invasion, and/or optic nerve invasion to transection consisted
of 53 patients, 35 of whom received adjuvant therapy and 18 who did not. Two
patients (6%) developed metastasis in the adjuvant therapy group, compared
with 7 (39%) in the group that did not receive adjuvant therapy (P = .005). The subgroup with massive choroidal infiltration, retrolaminar
optic nerve extension, invasion of optic nerve transection, scleral infiltration,
and/or extrascleral extension consisted of 56 patients. Thirty-eight of them
were provided adjuvant therapy, of whom 2 (5%) developed metastasis. Of 18
patients who did not receive any form of adjuvant therapy, 7 (39%) developed
metastasis (P = .003). Twenty-four patients had anterior
chamber seeding, iris infiltration, ciliary body infiltration, and/or invasion
of optic nerve lamina cribrosa as histopathologic risk factors. Twelve patients
in this group did not receive adjuvant therapy, of whom 1 developed metastasis
(P = .50).
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Table 4. Presence of High-Risk Characteristics on Histopathology and
Incidence of Metastasis in 80 Patients With Retinoblastoma
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COMMENT
The goals of management of retinoblastomas are, first, to save lives
and, second, to salvage the eye and vision if possible. Therapy is individualized
based on the overall clinical situation, including the risk for metastasis
and second malignant neoplasm, systemic condition, laterality of the disease,
size and location of the tumors, and visual prognosis. The available therapeutic
options for retinoblastoma include enucleation, external beam radiotherapy,
episcleral plaque brachytherapy, laser photocoagulation, laser thermotherapy,
cryotherapy, chemotherapy, and orbital exenteration, either individually or
in various combinations.1-2 Despite
recent advances in retinoblastoma treatment and the current trend in favor
of measures to salvage the eye and possibly vision, enucleation is still a
valid primary therapeutic option for advanced unilateral retinoblastoma.1-2 Primary enucleation performed under
such circumstances offers a high cure rate of 90% to 95%.21
Metastasis may still develop in 5% to 10% of patients undergoing primary enucleation
for advanced unilateral retinoblastoma in developed countries,1-5
and at a much higher rate in developing nations.6, 9
It may be possible to prevent metastasis by identifying patients with
risk factors predictive of metastasis and providing them with adjuvant therapy.
It seems reasonable to assume that micrometastases present at the time of
enucleation and residual orbital disease are the sources of subsequent systemic
metastasis. Given the inability to detect micrometastasis,36
and the extremely poor prognosis for overt metastasis,11
it may be appropriate to consider adjuvant chemotherapy to eradicate micrometastatic
disease. Notably, this strategy has been the basis of therapeutic success
in the improvement of prognosis for other childhood neoplasia.27
The identification of frequency and significance of histopathologic
risk factors that reliably predict metastasis is vital for patient selection
for adjuvant therapy. Several studies have addressed this issue.11-17,31
The reported occurrence of anterior chamber seeding (7%),14
massive choroidal infiltration (12%-23%),12-17,31
invasion of optic nerve lamina cribrosa (6%-7%),12-14,16, 31
retrolaminar optic nerve invasion (6%-12%),12-14,16, 31
invasion of optic nerve transection (1%-25%),12-14,16, 31
scleral infiltration (1%-8%),12, 14, 31
and extrascleral extension (2%-13%)12, 14, 31
varies widely even in developed countries. Vemuganti et al37
reported that 21% of the 76 eyes enucleated for advanced retinoblastoma in
India had anterior chamber seeding, while 54% had massive choroidal infiltration,
46% had optic nerve invasion at or beyond the optic nerve lamina cribrosa,
and 7% had scleral infiltration or extrascleral extension. This is strikingly
higher compared with the data from developed countries. It is now generally
agreed that massive choroidal infiltration, retrolaminar optic nerve invasion,
invasion of the optic nerve to transection, scleral infiltration, and extrascleral
extension are risk factors predictive of metastasis.6, 12-17,31
However, the role and significance of anterior chamber seeding, iris infiltration,
ciliary body infiltration, and invasion of the optic nerve lamina cribrosa
as risk factors for metastatic retinoblastoma remain debatable.6, 12-17,31
Studies initiated in the 1970s on adjuvant therapy to minimize the risk
of metastasis were marked by variable results and provided no firm recommendation.27 In a prospective randomized study by the Children's
Cancer Study Group, comprising 14 patients with high-risk retinoblastoma treated
with adjuvant chemotherapy, no significant difference in survival was demonstrable
in comparison with the control group.22 A prospective
study by Zelter et al26 also showed equivocal
results. Recently, Mustafa et al34 observed
that despite postenucleation and adjuvant chemotherapy with vincristine, doxorubicin,
and cyclophosphamide, patients with retinoblastoma having retrolaminar optic
nerve invasion had a low survival rate. Chantada et al,17
based on their study of patients with risk factors, stated that adjuvant chemotherapy
was not warranted in patients with prelaminar optic nerve invasion and probably
not in cases with retrolaminar optic nerve invasion and isolated choroidal
infiltration. On the contrary, several studies have indicated that adjuvant
chemotherapy was beneficial.21, 25, 28, 31-33
Howarth et al,21 in a small prospective series
of 14 patients, found a beneficial role of adjuvant chemotherapy for high-risk
retinoblastoma. Keith25 found benefit with
adjuvant chemotherapy in these patients, but issued a warning regarding the
possibility of chemotherapy-induced second malignant neoplasms.25
Hungerford28 commented that all children in
London, England, with massive choroidal infiltration or retrolaminar optic
nerve invasion had received systemic adjuvant chemotherapy since 1985, and
none of them had developed metastasis. Khelfaoui et al31
found a statistically significant decrease in retinoblastoma metastasis in
a diverse group of 75 patients treated with adjuvant chemotherapy.31 In a prospective evaluation by Schwartzman et al32 of a stage-based (Grabowski and Abramson38) protocol, it was found that adjuvant chemotherapy
was beneficial in cases with extraocular extension of retinoblastoma. An approach
of high-dose chemotherapy followed by hematopoietic stem cell rescue was beneficial
in a diverse group of patients with high-risk retinoblastoma, but results
were comparable to those of conventional, less aggressive protocols.33 Uusitalo et al39 concluded
that chemoprohylaxis is necessary for patients with tumor invasion of optic
nerve transection and is likely to be beneficial in preventing metastasis
in patients with retrolaminar optic nerve invasion.39
On reviewing the published literature regarding the role of adjuvant
therapy in high-risk retinoblastoma,21-34
it is evident that the major limitations of such studies have been the particular
rarity of the end point (metastasis),21, 25, 28, 33, 39
the lack of comparable stratification for subgroup analysis,21, 23, 25-26,28, 31-34
and more significantly, the absence of a control group (Table 5).21, 25-26,28, 32-34
The absence of strict inclusion criteria, the inclusion of a wide variety
of cases with bilateral and heritable retinoblastoma, and patients with multiple
prior treatments may have introduced confounding variables, making it difficult
to objectively interpret the results of these studies.21-34,39
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Table 5. The Role of Adjuvant Chemotherapy in Preventing Metastasis
in High-Risk Retinoblastoma: Survey of the Published Literature*
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The presence of histopathologically proven residual orbital retinoblastoma
(invasion of optic nerve transection and extraocular extension) may warrant
the use of orbital external beam radiotherapy.6
In addition, clinical circumstances that possibly increase the risk of microscopic
extraocular tumor cell seeding (scleral infiltration by the tumor, spontaneous
or accidental perforation of an eye with retinoblastoma, intraocular surgery
in an eye with unsuspected retinoblastoma) may also warrant using orbital
external beam radiotherapy.35 Shields et al35 have reported the beneficial effect of adjuvant orbital
external beam radiotherapy used in addition to systemic chemotherapy in preventing
metastasis in a group of children who had undergone intraocular surgery for
unsuspected retinoblastoma. However, to our knowledge, there are no studies
that have evaluated the role of adjuvant orbital external beam radiotherapy
in preventing metastasis in patients with histopathologically proven residual
orbital retinoblastoma.
In the absence of a randomized prospective controlled trial dealing
with the issue of adjuvant therapy, we believe that our large study with a
long-term follow-up (median, 59 months) provides useful information. One major
drawback of our study was that it was retrospective in nature and was nonrandomized.
We, however, had a concurrent control group of patients (Table 2) who met all the inclusion criteria but who did not receive
adjuvant therapy. We used specific predetermined histopathologic characteristics
for inclusion of patients into this study (Table 1). Our series consisted only of patients with unilateral
sporadic retinoblastoma who underwent primary enucleation. This was to eliminate
the influence of confounding factors such as tumor in the nonenucleated eye
in bilateral cases, and multiple prior therapy in cases with secondary enucleation
on the end point. However, our strict selection criteria may have resulted
in underestimation of the incidence of metastasis. A minimum follow-up of
1 year was established to allow inclusion of metastatic events that generally
occur at a mean of 9 months following enucleation.6
We found that administration of adjuvant therapy significantly reduced
the risk of metastasis in patients with histopathologic high-risk characteristics
as defined by our inclusion criteria. The adjuvant treatment was mainly determined
by the prevailing protocol of the treating oncologist. The group that received
adjuvant therapy was (understandably) selected for having a comparatively
higher risk of metastasis than the group that did not receive adjuvant therapy
(Table 2). Therefore, it seems
that adjuvant therapy resulted in a significant reduction in the incidence
of metastasis that was below that of the relatively low-risk group that was
not provided adjuvant therapy.
It is possible that not all the histopathologic factors are equivalent
in their risk for metastasis. The statistical analysis was limited by the
small number of patients and the infrequent number of events (metastasis)
in each subgroup. The beneficial effect of adjuvant therapy in preventing
metastasis was statistically significant in the presence of massive choroidal
infiltration or retrolaminar optic nerve invasion. The benefit was also statistically
significant in the subgroup having any degree of optic nerve invasion beyond
the lamina cribrosa (retrolaminar optic nerve invasion and invasion of optic
nerve transection). We were unable to analyze the beneficial effect of adjuvant
therapy on individuals in groups with invasion of optic nerve transection
and extrascleral extension because all of the patients with these risk factors
had been provided with adjuvant therapy. We found that the adjuvant therapy
was most beneficial when massive choroidal infiltration, retrolaminar optic
nerve invasion, invasion of optic nerve transection, scleral infiltration,
and/or extrascleral extension were present. It is, however, difficult to completely
negate the role of the other histopathologic factors, such as anterior chamber
seeding, iris infiltration, ciliary body infiltration, and invasion of optic
nerve lamina cribrosa in causing metastasis.
Various combinations of chemotherapeutic drugs have been used in the
past (Table 5).21-34
Throughout the years, we have used a combination of vincristine, doxorubicin,
and cyclophosphamide or a combination of vincristine, carboplatin, and etoposide
(Table 3). The baseline characteristics
of the groups that received 2 chemotherapy regimens were comparable. The difference
in the beneficial effects of the 2 drug regimens could not be evaluated because
of the small number of patients who developed metastasis. Questions regarding
the safety of chemotherapy involved systemic toxic effects and possible increased
risk of second malignant neoplasms with cytotoxic therapy.40
None of the patients in our series suffered irreversible systemic toxic effects
with either of the drug regimens. There was no second malignant neoplasm observed
in our series, which comprised cases of unilateral retinoblastomas at a median
follow-up of 59 months. The question regarding possible induction of second
malignant neoplasms in a susceptible patient population could be answered
only by large controlled long-term studies. Based on our results, we cannot
comment on the ideal drug regimen for adjuvant therapy. A combination of vincristine,
doxorubicin, and cyclophosphamide has the advantage of being relatively less
expensive, and potentially has fewer severe systemic adverse effects. However,
carboplatin has high penetration into the central nervous system and bone
marrow,28 which are the 2 potential sites of
metastasis. Combining carboplatin with etoposide is synergistic when used
for embryonal neuroectodermal tumors in children.30
Some of the patients who received adjuvant chemotherapy additionally
received orbital external beam radiotherapy. It is difficult to analyze and
comment on the individual role of adjuvant chemotherapy and adjuvant orbital
external beam radiotherapy in preventing systemic metastasis. Each modality
may have potentiated the beneficial effect of the other in preventing systemic
metastasis.
Our current practice is to administer 6 cycles of a combination of carboplatin,
etoposide, and vincristine (identical to the protocol used for chemoreduction
of intraocular retinoblastoma)18 in patients
with histopathologic risk factors for metastasis (Table 1). We currently do not use adjuvant intrathecal methotrexate.
All patients with invasion of optic nerve transection, scleral infiltration,
and extrascleral extension currently receive adjuvant orbital external beam
radiotherapy.
In summary, we found that adjuvant therapy was effective in significantly
reducing the risk of metastasis in high-risk cases of retinoblastoma. The
incidence of metastasis was 4% in those who received adjuvant therapy, compared
with 24% in those who did not. Based on the results of our study, it is reasonable
to conclude that adjuvant therapy is beneficial in reducing the risk of metastasis
in cases of retinoblastoma with high-risk characteristics on histopathology
reports. The beneficial effect of adjuvant therapy seems pronounced in the
subgroup of patients with massive choroidal infiltration and retrolaminar
optic nerve invasion. A large randomized multicentric prospective study may
help in resolving some of the outstanding issues that include stratification
of risk factors and identification of a specific subset of high-risk characteristics
in the presence of which postenucleation adjuvant therapy may be most beneficial.
AUTHOR INFORMATION
Submitted for publication July 17, 2001; final revision received March
4, 2002; accepted March 20, 2002.
This study was supported by the L. V. Prasad Eye Institute, Hyderabad
Eye Research Foundation, Hyderabad, India (Dr Honavar); Orbis International,
New York, NY (Dr Honavar); the Paul Kayser International Award of Merit in
Retina Research, Houston, Tex (Dr J. A. Shields); and the Eye Tumor Research
Foundation, Philadelphia, Pa (Drs C. L. Shields and J. A. Shields).
This study was presented in part at the annual meeting of the Association
for Research in Vision and Ophthalmology, Fort Lauderdale, Fla, April 30-May
5, 2000, and at the Annual Meeting of the American Academy of Ophthalmology,
Dallas, Tex, October 22-25, 2000.
Corresponding author and reprints: Arun D. Singh, MD, Oncology Service,
Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107 (e-mail: arunsingh{at}eyetumors.com).
From the Oncology Service, Wills Eye Hospital, Thomas Jefferson University,
Philadelphia, Pa (Drs Honavar, Singh, C. L. Shields, Demirci, and J. A. Shields);
Ocular Oncology Service, L. V. Prasad Eye Institute, Hyderabad, India (Dr
Honavar); Royal Hallamshire Hospital, Sheffield, England (Dr Singh); Division
of Oncology, Children's Hospital of Philadelphia, Philadelphia (Dr Meadows);
and Biomedical Statistical Consulting, Cherry Hill, NJ (Dr Cater). The authors
do not have a proprietary interest in any of the materials or methods used
in this study.
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1. Shields JA, Shields CL. Introacular Tumors: A Text and Atlas. Philadelphia, Pa: WB Saunders Co; 1992:377-391.
2. Shields CL, Shields JA. Recent developments in the management of retinoblastoma. J Pediatr Ophthalmol Strabismus. 1999;36:8-18.
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