Incidence of New Tumor Formation in

Patients with Hereditary Retinoblastoma

Treated with Primary Systemic Chemotherapy:
Is There a Preventive Effect?
Matthew W. Wilson, MD, FACS,1,2,3 Barrett G. Haik, MD, FACS,1,2 Catherine A. Billups, MS,4
Carlos Rodriguez-Galindo, MD5,6
Purpose: To report the incidence of new tumor formation in hereditary retinoblastoma patients treated with
primary systemic chemotherapy.
Design: Noncomparative retrospective case series.
Participants: Fifty-eight consecutive patients with hereditary retinoblastoma treated with primary systemic
chemotherapy.
Methods: The charts of 58 consecutive patients with hereditary retinoblastoma treated between January 1996
and August 2005 were reviewed. Data extracted included gender, age at diagnosis, family history of retinoblastoma,
laterality of disease, tumors per eye, ReeseEllsworth grouping of affected eyes, starting and ending dates for
chemotherapy, number of cycles of chemotherapy, chemotherapy regimen, need for external beam radiotherapy
and/or enucleation, and development and location (macula, midzone, and periphery) of new tumors after the start of
systemic chemotherapy.
Main Outcome Measure: New tumor formation after treatment with primary systemic chemotherapy.
Results: Of the 58 patients, 48 had bilateral involvement at diagnosis. Median age at diagnosis was 6.6 months.
Thirteen patients had a positive family history. Of the eyes with tumor (n 106) at diagnosis, 52 (49%) were in
ReeseEllsworth groups I to III, whereas 54 (51%) were in group IV or V. Seven patients (12%) with a median age of
1.6 months at diagnosis formed 36 new tumors in 11 eyes after the start of chemotherapy. Median time from initiation
of chemotherapy to detection of the first new tumor was 3 months (range, 115). Cumulative incidence of new tumor
formation at 2 years was 103%. An age of 6 months at diagnosis, family history of retinoblastoma, and
ReeseEllsworth grouping of I to III were found to correlate significantly with an increased incidence of new tumor
formation (P0.001, P0.001, and P 0.021, respectively). Median follow-up for all patients was 5 years (range, 110.1).
Conclusion: New tumors continue to form in patients with hereditary retinoblastoma despite treatment with
primary systemic chemotherapy. Younger patients and those with a positive family history are more likely to have new
tumors formed. However, chemotherapy may impact small previously undetected lesions by slowing their growth and
facilitating later focal consolidation. Ophthalmology 2007;114:20772082 2007 by the American Academy of
Ophthalmology.

Retinoblastoma is the most common intraocular malignancy

of childhood.1 Approximately 1 in 20 000 live births is
affected annually, with 300 new cases being diagnosed in
the United States each year.1 One third of these children will

have bilateral/multifocal intraocular retinoblastoma. Such

patients are referred to as having hereditary retinoblastoma,
as they possess a germline mutation in one allele of the RB1
5

Originally received: November 8, 2006.

Final revision: February 13, 2007.
Accepted: March 7, 2007.
Available online: July 12, 2007.
Manuscript no. 2006-1295.
1
Department of Ophthalmology/Hamilton Eye Institute, University of
Tennessee Health Science Center, Memphis, Tennessee.
2
Division of Ophthalmology, Department of Surgery, St. Jude Childrens
Research Hospital, Memphis, Tennessee.
3
Department of Pathology, St. Jude Childrens Research Hospital, Memphis, Tennessee.
4
Department of Biostatistics, St. Jude Childrens Research Hospital, Memphis, Tennessee.
2007 by the American Academy of Ophthalmology
Published by Elsevier Inc.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee.

6
Department of Oncology, St. Jude Childrens Research Hospital, Memphis, Tennessee.
Presented at: American Academy of Ophthalmology Annual Meeting,
November 13, 2006, Las Vegas, Nevada.
Supported by the National Cancer Institute, Bethesda, Maryland (grant nos.
CA 23099, 21765 [Cancer Center Support Grant]); American Lebanese Syrian
Associated Charities, Memphis, Tennessee; Research to Prevent Blindness,
New York, New York; and St. Giles Foundation, New York, New York.
Correspondence to Matthew W. Wilson, Hamilton Eye Institute, 930
Madison Avenue, Room 476, Memphis, TN 38163. E-mail:
mwilson5@utmem.edu.
ISSN 0161-6420/07/$see front matter
doi:10.1016/j.ophtha.2007.03.015

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Ophthalmology Volume 114, Number 11, November 2007

gene. The median age at diagnosis for these patients is 1
year.1 During their course of treatment, new tumors will
form throughout the retina, most often peripheral to the
macula.2 The younger the patient is at diagnosis, the greater
the risk for new tumors to form.3 External beam radiotherapy (EBR) was the mainstay of treatment for these patients
until the 1990s. Although it would seem that radiation
would sterilize the entire retina and, thus, decrease the risk
for new tumor formation, retrospective studies have shown
differently, with the risk remaining unchanged.4 7
The risk of second malignancies from EBR led investigators to seek alternative treatment strategies in patients with
hereditary retinoblastoma.8 In the past decade, radiationsparing therapies that incorporate primary systemic chemotherapy and aggressive focal consolidation with cryotherapy, transpupillary thermotherapy, and brachytherapy have
evolved.9 19 The success of these approaches has been
extensively reported and additional benefits observed. Most
notable has been a decrease in the incidence of secondary
pineal tumors, suggesting a possible protective effect from
the chemotherapy.20 Further studies have examined the
impact of primary systemic chemotherapy on new tumor
formation in the eyes. These studies have shown that new
tumors continue to develop both during and after the completion of chemotherapy in up to 48% of treated eyes. New
tumors form most often within 5 months of the completion
of chemotherapy. Patients diagnosed at an earlier age remain at a greater risk for new tumors to form.2123 We have
studied the rate of new tumor formation in patients treated
with systemic chemotherapy and, herein, report our findings
in 116 eyes of 58 patients with hereditary retinoblastoma.

Materials and Methods

Approval was obtained from the institutional review board at St.
Jude Childrens Research Hospital to review retrospectively the
medical records of 58 consecutive patients with hereditary retinoblastoma treated with primary systemic chemotherapy between
January 1996 and August 2005. The following patient data were
extracted: gender, age at diagnosis, family history of retinoblastoma, laterality of disease, tumors per eye, ReeseEllsworth grouping of affected eyes, starting and ending dates for chemotherapy,
number of cycles of chemotherapy, chemotherapy regimen, need
for EBR and/or enucleation, and development and location (macula, midzone, and/or periphery) of new tumors after the start of
systemic chemotherapy. New tumors were defined as those lesions
that developed remote to another tumor. Tumors adjacent to a flat
chorioretinal scar from prior treatment were excluded. Multiple
grouped new tumors in the presence of overt vitreous and/or
subretinal seeds were recorded as implantations and not subject to
analysis in this study. The main outcome measured was the development of new tumors after the start of chemotherapy.

Statistical Methods
The association between ReeseEllsworth group at diagnosis (I/
II/III vs. IV/V) and number of tumors at diagnosis was investigated
using the exact Wilcoxon rank sum test. The Spearman correlation
coefficient was used to examine the association between age at
diagnosis and number of tumors. The cumulative incidence of new
tumor formation was estimated. Although interocular correlation

2078

may exist in patients with bilateral disease,24 the eye was chosen
as the unit of analysis. For eyes with multiple new tumors, the date
of first new tumor formation was used. Enucleation and EBR
before new tumor formation were considered as competing events
in this analysis. Eyes that did not develop new tumors and did not
have other events (enucleation or EBR) were censored at the date
of last follow-up. The Gray test was used to test whether youngness, ReeseEllsworth group, and family history impacted new
tumor formation.25 P values and test statistics (with corresponding
degrees of freedom) resulting from the Gray tests were reported.
This was an exploratory retrospective study, and P values should
be interpreted with caution; no adjustments were made for multiple
tests.

Results
All 58 patients were observed with serial examinations under
anesthesia inclusive of digital fundus photography based on age
and stability of disease. Of them, 34 were male and 13 had a family
history of retinoblastoma (Table 1). Patients median age at
diagnosis was 6.6 months (range, 0.237.3). Forty-eight patients presented with bilateral retinoblastoma. Of the 106 eyes
with retinoblastoma at diagnosis, 52 were classified as being in
ReeseEllsworth groups IIII and 54 were classified as being in
ReeseEllsworth group IV or V. Most eyes were in group V at
diagnosis (n 50 eyes [47%]). There were a total of 237 tumors
at diagnosis in 106 eyes in 58 children. For the 106 eyes with
tumors at diagnosis, the median number of tumors per eye was 2
(range, 19). There was no evidence of an association between
ReeseEllsworth group at diagnosis (I/II/III vs. IV/V) and number
of tumors at diagnosis (P 0.98). There was also no evidence of
an association between age at diagnosis and total number of
tumors in patients (P 0.55, 0.08).
All patients were alive at the time of analysis, with a median
follow-up from diagnosis of 5.0 years (range, 1.0 10.1). Seven
patients (12%) developed a total of 36 new tumors in 11 eyes
(Tables 2, 3 [available at http://aaojournal.org]); 6 tumors formed
in the macula, 16 in the midzone, and 14 in the periphery. The
median time from start of chemotherapy to detection of the first
new tumor was 3 months (range, 115); the latest time a new
tumor was noted to form was 24 months from the start of chemotherapy. One of these 7 patients had bilateral disease at diagnosis
and developed new tumors in both eyes approximately 1 month
after starting chemotherapy. The other 6 patients had unilateral
disease at diagnosis. Three of these 6 patients developed new
tumors in the opposite eye at approximately 3.0, 7.2, and 7.5
months after initiation of chemotherapy. The other 3 patients
developed new tumors in both eyes. Of note, none of these eyes
had EBR before development of new tumors. In addition, none of
these eyes were subsequently enucleated.
Cumulative incidences of new tumor formation at 1 and 2 years
were estimated to be 83% and 103%, respectively. Figure 1
shows the cumulative incidence of new tumor formation for all
eyes. Family history was a significant predictor of new tumor
formation (P0.001, 21 17.8). Eyes of patients with a family
history were more likely to develop new tumors than eyes of
patients without a family history; 2-year cumulative incidences
were 319% and 32% for eyes with and without family histories, respectively (Fig 2). Age at diagnosis was also a significant
predictor of new tumor formation (P0.001, 21 13.9). Eyes in
patients who were younger than 6 months at diagnosis were more
likely to develop new tumors (2-year cumulative incidence,
216%) than eyes in patients who were at least 6 months old at
diagnosis (2-year cumulative incidence, 00%) (Fig 3). All pa-

Wilson et al Incidence of New Tumor Formation after Systemic Chemotherapy

Table 1. Patient and Treatment Characteristics
Characteristic

retinoblastoma at diagnosis were studied. There was evidence that

the ReeseEllsworth grouping was a significant predictor of new
tumor formation (P 0.021, 21 5.3). All 5 eyes that had
retinoblastoma at diagnosis and later formed new tumors had a low
ReeseEllsworth classification, either group I (3 eyes) or group II
(2 eyes). The cumulative incidence of new tumor formation was
104% for ReeseEllsworth groups I to III, versus 00% for
ReeseEllsworth group IV or V (Fig 4).

N (%)

Gender
Male
Female
Age at diagnosis (mos)
Birth to 1
13
36
69
912
1215
1518
1821
2124
24
Unilateral
Bilateral
Family history
No
Yes
Chemotherapy
VC 4
VC 6
VC 7
VC 8
VC 8 VCE 3
VC 8 VT 3
VCE 6
ReeseEllsworth classification at diagnosis (n 106 eyes)
I
II
III
IV
V

34 (59%)
24 (41%)
6 (10%)
10 (17%)
11 (19%)
7 (12%)
10 (17%)
3 (5%)
0 (0%)
4 (7%)
3 (5%)
4 (7%)
10 (17%)
48 (83%)

Discussion
It has been estimated that hereditary retinoblastoma patients
will develop, on average, 2.7 tumors per eye.2 New tumors
will continue to form after initial diagnosis. Whether a
patients genetic predisposition to form new tumors can be
altered by treatment is unknown. We studied the impact of
primary systemic chemotherapy on the rate of new tumor
formation in a cohort of 58 patients with hereditary retinoblastoma. We found an overall cumulative incidence of 10%
at 2 years after the start of chemotherapy. Younger age at
diagnosis, family history of retinoblastoma, and lower
ReeseEllsworth classification were factors that significantly increased the likelihood of new tumor formation (P
0.001, P 0.001, and P 0.021, respectively). Eyes of
patients with a family history had a 31% incidence of new
tumor formation at 2 years, whereas those patients diagnosed before 6 months of age had a 21% incidence. Eyes
classified as ReeseEllsworth groups I to III had a 10%
incidence of new tumors. Each of these risk factors is intrinsically tied together. Patients with a family history are more
likely to be screened starting at birth and therefore diagnosed at
a younger age with less advanced intraocular disease.
We observed 36 new tumors in 11 eyes. Of these, 17%
(n 6) were in the macula, 44% (n 16) were in the
midzone, and 39% (n 14) were in the periphery. New
tumor formation in retinoblastoma appears to be closely tied
to retinal development. Immature retinal cells remain susceptible to second random mutations leading to inactivation
of the retinoblastoma protein and tumor development. As
the retina matures from the posterior pole towards the

45 (78%)
13 (22%)
1 (2%)
1 (2%)
5 (9%)
44 (76%)
2 (3%)
2 (3%)
3 (5%)
15 (14%)
24 (22%)
13 (12%)
4 (4%)
50 (47%)

C carboplatin; E etoposide; T topotecan; V vincristine.

tients who developed new tumors were younger than 5 months at

their initial diagnosis.
ReeseEllsworth classification was also investigated as a predictor of new tumor formation. Because many new tumors formed
in eyes with no disease at diagnosis, only the 106 eyes with
0.20

0.15

0.10

0.05

0.00
0

10

12

Figure 1. Cumulative incidence estimates of new tumor formation for all eyes (n 116). X-axis, years.

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Ophthalmology Volume 114, Number 11, November 2007

Figure 2. Cumulative incidence estimates of new tumor formation by family history (yes [solid line] vs. no [dashed line]) (P0.001, 21 17.8). X-axis,
years.

periphery, the majority of new tumors form outside the

macula closer to the midzone and periphery.
Whether these new tumors developed before, during, or
after chemotherapy is uncertain. One hypothesis is that each
new tumor represents a new mutation that occurred after the
start of chemotherapy and the tumor grew unimpeded. Alternatively, these small tumor foci may have preceded the
start of chemotherapy and not been detected. Their poorly

developed intrinsic vascularity may not have allowed cytotoxic levels of the chemotherapeutic agents to be achieved.
In these instances, the tumors growth may have been
blunted, but it continued to grow either at the completion of
chemotherapy or once resistance had been developed. This
hypothesis is in keeping with the finding of Gombos et al
that tumors 2 mm in diameter are less likely to respond to
chemotherapy.26 They concluded that the poorly developed

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0.00
0

10

12

Figure 3. Cumulative incidence estimates of new tumor formation by age at diagnosis (6 months [solid line] vs. 6 months [dashed line]) (P0.001,
21 13.9). X-axis, years.

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Wilson et al Incidence of New Tumor Formation after Systemic Chemotherapy

0.20

0.15

0.10

0.05

0.00
0

10

12

Figure 4. Cumulative incidence estimates of new tumor formation by ReeseEllsworth classification (I/II/III [solid line] vs. IV/V [dashed line]) (P 0.021,
21 5.3). X-axis, years.

vasculature of small tumors did not allow adequate delivery

of the systemic chemotherapy. We believe that both of these
hypotheses account for tumors detected after the administration of systemic chemotherapy in our patients.
Ours was not the first study to address the impact of
treatment on the new tumor formation in patients with
hereditary retinoblastoma. Initial reports pertained to those
patients treated with EBR. Salmonsen et al reported that
11% of eyes with retinoblastoma treated with EBR developed new tumors at a mean of 3.5 months after treatment.4
Of the 61 tumors documented, 90% were in the periphery of
the retina. Their findings led them to hypothesize that
retinoblastoma has the propensity to develop in the immature retina, and thus, tumor development follows the
progression of retinal development from the posterior
pole to the ora serrata. Later, Merrill et al reported similar
findings over a 10-year study period, with an overall 13%
incidence of new tumor formation after EBR.5 However,
when patients were stratified by age, a 25% risk for those
patients diagnosed before 6 months of age was found.
Other studies have shown similar rates of new tumor
formation after EBR.6,7
Abramson et al studied 355 eyes from 325 patients with
bilateral retinoblastoma treated with modalities other than
enucleation, inclusive of EBR, intraarterial chemotherapy,
plaque brachytherapy, photocoagulation, and cryotherapy.
New tumors formed in 25% of the eyes.3 Patients diagnosed
before 6 months of age had a 45% chance of developing
new tumors, as compared with a 14% chance in those
patients diagnosed after 6 months of age. Patients diagnosed
before 2 years of age were noted to develop tumors up to 4.5
years after treatment, whereas those patients diagnosed after
2 years of age developed tumors up to 1.5 years later. A
later study by the same authors focused on new intraocular
tumors after treatment in patients with unilateral retinoblastoma.27 In contrast to their previous study, those patients
treated with enucleation were included. Overall, 6% of the
patients developed at least one new tumor in either the
treated or the untreated eye. Patients with a family history of
retinoblastoma and those patients diagnosed before 6
months of age had the greatest risk: 35% and 16%, respectively. In that study, the mean time to new tumor formation
after treatment was 0.74 years; no new tumors developed
after 7.7 years of age.

In the era of primary systemic chemotherapy for the

treatment of intraocular retinoblastoma, Scott et al were the
first to report the occurrence of new tumors.28 Four children
were found to develop 9 new tumors in 6 eyes either during
or after the completion of chemotherapy. The small series
did not permit statistical analysis but did alert us to the need
for continued close surveillance both during and after the
completion of chemotherapy. Lee et al later reported their
findings in 57 eyes of 34 patients with hereditary retinoblastoma treated initially with systemic carboplatin.21
They observed 63 new tumors in 27 eyes (47%). Of the
new tumors noted, 57% formed within months of carboplatin treatment. As in previous studies, children diagnosed before 6 months of age were at a greater risk for
new tumor formation in comparison to those diagnosed
later: 60% and 31%, respectively. The majority of new
tumors formed before 1 year of age and were detected
within 4 months of chemotherapy. Shields et al also
studied the impact of systemic chemotherapy on new
tumor formation in 162 eyes of 106 patients.22 According
to KaplanMeyer analysis, new tumors formed in 23% of
patients treated with 6 cycles of carboplatin, vincristine,
and etoposide within 1-year follow-up and in 24% by
5-year follow-up. The mean interval for new tumor formation was 5 months after diagnosis. Familial history
and younger age at diagnosis were the most important
risk factors by multivariate analysis. More recently,
Schueler et al have published their findings on 50 eyes of
32 patients with hereditary retinoblastoma treated with a
mean of 6 cycles of triple-agent chemotherapy (vincristine, etoposide, carboplatin, or cyclophosphamide).23
New tumors occurred in 48% of the eyes treated either
during or within 7 months after completion of chemotherapy. Children who developed new tumors were significantly younger at the time of diagnosis and had a
significantly lower number of tumors per eye at diagnosis. In our own study as well as those cited above, not all
patients were treated with the same chemotherapeutic
regimens. Therefore, we can only discuss the effects of
primary systemic chemotherapy in a general context
without regard to specific chemotherapeutic agents.
Even though the reported risk for new tumor formation
varies in each of the aforementioned studies, we believe the
findings are similar to ours. Incidences of new tumor for-

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Ophthalmology Volume 114, Number 11, November 2007

mation among the eyes treated with systemic chemotherapy,
EBR, or focal therapies do not differ. Thus, it would appear
that neither chemotherapy nor radiation alters a hereditary
retinoblastoma patients predisposition to form new tumors.
In theory, only therapies that specifically targeted retinal
development would be able to prevent new tumors from
occurring. Nonetheless, we do believe systemic chemotherapy impacts the growth of small undetected lesions by
slowing their growth and facilitating later focal consolidation. Close surveillance with serial examinations under anesthesia with meticulous attention to the developing peripheral retina remains mandatory.

References
1. Ellsworth RM. The practical management of retinoblastoma.
Trans Am Ophthalmol Soc 1969;67:462534.
2. Abramson DH, Gombos DS. The topography of bilateral
retinoblastoma lesions. Retina 1996;16:2329.
3. Abramson DH, Greenfield DS, Ellsworth RM. Bilateral
retinoblastoma: correlations between age at diagnosis and time
course for new intraocular tumors. Ophthalmic Paediatr Genet
1992;13:17.
4. Salmonsen PC, Ellsworth RM, Kitchin FD. The occurrence of
new retinoblastoma after treatment. Ophthalmology 1979;86:
837 43.
5. Merrill PT, Buckley EG, Halperin EC. New and recurrent
tumors in germinal retinoblastoma: is there a treatment effect?
Ophthalmic Genet 1996;17:115 8.
6. Hernandez JC, Brady LW, Shields JA, et al. External beam
radiation for retinoblastoma: results, patterns of failure and a
proposal for treatment guidelines. Int J Radiat Oncol Biol
Phys 1996;35:12532.
7. Messmer EP, Sauerwein W, Heinrich T, et al. New and recurrent
tumor foci following local treatment as well as external beam
radiation in eyes of patients with hereditary retinoblastoma.
Graefes Arch Exp Clin Exp Ophthalmol 1990;228:426 31.
8. Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on
radiation-related risk. Ophthalmology 1998;105:5739.
9. Wilson MW, Rodriguez-Galindo C, Haik BG, et al. Multiagent chemotherapy as neoadjuvant treatment for multifocal
intraocular retinoblastoma. Ophthalmology 2001;108:2106
14, discussion 2114 5.
10. Rodriguez-Galindo C, Wilson MW, Haik BG, et al. Treatment
of intraocular retinoblastoma with vincristine and carboplatin.
J Clin Oncol 2003;21:2019 25.
11. Shields CL, De Potter P, Himelstein B, et al. Chemoreduction
in the initial management of intraocular retinoblastoma. Arch
Ophthalmol 1996;114:1330 8.
12. Friedman DL, Himelstein B, Shields CL, et al. Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 2000;18:127.

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13. Gallie BL, Budning A, DeBoer G, et al. Chemotherapy with

focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 1996;114:1321 8.
14. Murphree AL, Villablanca JG, Deegan WF III, et al. Chemotherapy plus local treatment in the management of intraocular
retinoblastoma. Arch Ophthalmol 1996;114:1348 56.
15. Kingston JE, Hungerford JL, Madreperla SA, Plowman PN.
Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol 1996;
114:1339 43.
16. Greenwald MJ, Strauss LC. Treatment of intraocular retinoblastoma with carboplatin and etoposide chemotherapy. Ophthalmology 1996;103:1989 97.
17. Shields CL, Shields JA, Needle M, et al. Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma.
Ophthalmology 1997;104:210111.
18. Beck MN, Balmer A, Dessing C, et al. First-line chemotherapy with local treatment can prevent external-beam irradiation
and enucleation in low-stage intraocular retinoblastoma. J Clin
Oncol 2000;18:28817.
19. Brichard B, De Bruycker JJ, De Potter P, et al. Combined
chemotherapy and local treatment in the management of
intraocular retinoblastoma. Med Pediatr Oncol 2002;38:
4115.
20. Shields CL, Meadows AT, Shields JA, et al. Chemotherapy
for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol 2001;
119:1269 72.
21. Lee TC, Hayashi NI, Dunkel IJ, et al. New retinoblastoma
tumor formation in children initially treated with systemic
carboplatin. Ophthalmology 2003;110:1989 94.
22. Shields CL, Shelil A, Cater J, et al. Development of new
retinoblastoma after 6 cycles of chemoreduction for retinoblastoma in 162 eyes of 106 consecutive patients. Arch Ophthalmol 2003;121:1571 6.
23. Schueler AO, Anastassiou G, Jurklies C, et al. De novo
intraocular retinoblastoma development after chemotherapy
in patients with hereditary retinoblastoma. Retina 2006;26:
42531.
24. Chaum E, Ellsworth RM, Abramson DH, et al. Cytogenetic
analysis of retinoblastoma: evidence for multifocal origin and
in vivo gene amplification. Cytogenet Cell Genet 1984;38:
8291.
25. Gray RJ. A class of K-sample tests for comparing the cumulative
incidence of a competing risk. Ann Stat 1988;16:114154.
26. Gombos DS, Kelly A, Coen PG, et al. Retinoblastoma treated
with primary chemotherapy alone: the significance of tumour
size, location and age. Br J Ophthalmol 2002:86:80 3.
27. Abramson DH, Gamell LS, Ellsworth RM, et al. Unilateral
retinoblastoma: new intraocular tumours after treatment. Br J
Ophthalmol 1994;78:698 701.
28. Scott IU, Murray TG, Toledano S, OBrien JM. New retinoblastoma tumors in children undergoing systemic chemotherapy [letter]. Arch Ophthalmol 1998;116:1685 6.

Wilson et al Incidence of New Tumor Formation after Systemic Chemotherapy

Table 2. Patients with New Tumor Formation after the Start of Chemotherapy
Patient

Gender

Age at Diagnosis (mos)

Laterality

Family History

Duration of Chemotherapy (mos)

Chemotherapy Agents

1
2
3
4
5
6
7

M
F
F
M
M
M
F

4.8
1.5
0.3
1.6
0.2
2.8
2.8

Unilateral
Unilateral
Unilateral
Unilateral
Unilateral
Bilateral
Unilateral

No
No
Yes
Yes
Yes
Yes
No

5.8
5.1
11.0
9.5
5.0
9.5
6.4

VC 8
VC 8
VC 8 VT 3
VC 8 VCE 3
VC 8
VC 8 VT 3
VC 8

C carboplatin; E etoposide; F female; M male; T topotecan; V vincristine.

Table 3. Eyes with New Tumor Formation

ReeseEllsworth
Group

Age at
Diagnosis (mos)

Age at First
New Tumor (mos)

Total No. of New

Tumors
Identified

Ia

4.8
1.5
0.3
0.3
1.6

12
9
3
6
3

1
1
1
2
9

1.6

15

Right

0.2

5
6

Left
Right

1
3

Ia
IIa

0.2
2.8

15
4

1
10

Left

IIa

2.8

Right

2.8

Patient

Eye

Tumors at
Diagnosis

1
2
3
3
4

Left
Right
Right
Left
Right

0
0
1
0
1

Left

Ia

New Tumor
Location
Periphery, 1
Macula, 1
Midzone, 1
Macula, 2
Macula, 1;
midzone, 4;
periphery, 4
Macula, 1;
midzone, 3;
periphery, 1
Macula, 1;
midzone, 1
Midzone, 1
Midzone, 4;
periphery, 6
Midzone, 2;
periphery, 1
Periphery, 1

Time from
Chemotherapy
Start to First New
Tumor (mos)
7
7
2
5
1
13
3
15
1
1
3

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