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Clinical Sciences |

Outcome Following Initial External Beam Radiotherapy in Patients WithReese-Ellsworth Group Vb Retinoblastoma FREE

David H. Abramson, MD; Katherine L. Beaverson, MS; Sidney T. Chang, BA; Ira J. Dunkel, MD; Beryl McCormick, MD
[+] Author Affiliations

From the Department of Ophthalmology, New York Presbyterian Hospital–WeillMedical College of Cornell University (Dr Abramson, Ms Beaverson, and Mr Chang),and the Departments of Surgery (Dr Abramson), Pediatrics (Dr Dunkel), RadiationOncology (Dr McCormick), and Medicine (Ms Beaverson), Memorial Sloan-KetteringCancer Center, New York. The authors have no relevant financial interest inthis article.


Arch Ophthalmol. 2004;122(9):1316-1323. doi:10.1001/archopht.122.9.1316.
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Objective  To describe patient and ocular outcomes following initial treatmentwith external beam radiotherapy (EBT) in eyes with Reese-Ellsworth group Vbretinoblastoma.

Methods  Retrospective case series (from January 1, 1979, to February 28, 2002).The Kaplan-Meier method was used to analyze survival (ocular and patient)and incidence (second cancer) data.

Results  Two hundred forty-three patients with 1 or more Reese-Ellsworth groupVb eyes were identified. Of 284 group Vb eyes, 63 (22.2%) initially receivedEBT, vs 172 (60.6%) that were initially enucleated. Of the 63 radiated groupVb eyes, 31 (49.2%) had no further tumor growth, 26 (41.3%) developed a recurrence,and 8 (12.7%) developed a new tumor. Of the 63 radiated group Vb eyes, 33(52.4%) developed ocular complications. The ocular survival rate of radiatedgroup Vb eyes was 81.4% at 1 year and 53.4% at 10 years. Twenty-eight radiatedgroup Vb eyes survived to the last follow-up with visual acuity information.Thirteen patients developed second cancers, 11 in the field of radiation.The probability of developing a second cancer following initial EBT for groupVb disease in patients with bilateral disease was 29.7% by 10 years afterdiagnosis. Survival from second cancers in patients with bilateral diseaseinitially receiving EBT for group Vb disease was 93.6% at 5 years and 52.6%at 18¼ years. No patient with unilateral disease developed a secondcancer. Deaths due to metastatic retinoblastoma were uncommon.

Conclusions  To our knowledge, this is the first study focusing exclusively on groupVb eyes treated initially with EBT, most of which were salvaged with vision.Outcome data provided herein are clinically relevant when choosing treatmentoptions for advanced intraocular retinoblastoma.

Figures in this Article

It has been 100 years since the first report1 ofthe successful treatment of intraocular retinoblastoma (RB) with radiation.Since then, there has been an abundance of articles on the subject in theophthalmic and radiation oncology literature. Virtually every major figurein ophthalmic oncology worldwide, and every major center, has contributedto this literature.

It took more than 50 years to determine the optimal dose, dose rate,portals, fractionation scheme, and energy to correctly treat RB; as a resultof these advances, more eyes with RB were salvaged and more children retainedsight, in addition to being cured of their cancer. Retinoblastoma is a solidcancer of childhood that may be routinely cured with radiation alone.

In the early years of radiation therapy, the cancer was cured, but radiation-inducedcomplications were common. Enucleations following radiation were more oftenbecause of these complications than because the treatment failed to controlthe tumors.2,3 For more than 30years, however, ocular complications have been uncommon. The anterior segmentcomplications (other than cataract) are no longer seen, and radiation vasculopathyis so rare that recent series48 nolonger mention it as an event that occurred in treated patients. With therecognition that the orbital growth problems are minimal when radiation iswithheld until the age of 6 to 12 months, even this untoward effect has becomeless common.9

While ocular complications following radiation have been reduced, itis known that radiation plays a role in the genesis of subsequent primarymalignancies, so-called second nonocular tumors, in patients who receive externalbeam radiotherapy (EBT) as a treatment modality for RB. These additional malignanciesare associated with germline RB gene (RB1) defects;patients with unilateral disease who do not harbor a germline RB1 mutation do not develop these second cancers after radiation.10 Among the patients with a germline RB1 mutation who receive radiation, we know the following: (1) theincidence of subsequent nonocular cancers is hundreds of times more commonthan in the general pediatric population,11 (2)there is a dose-response curve for sarcomas in the field,12 (3)there is an increased incidence in children who undergo radiation in the firstyear of life,13,14 and (4) thereis an alteration in the timing and location of where the cancers occur inthe patient who has undergone radiation, especially in the first year of life.Without radiation, children with heritable RB develop one third of the secondcancers in the field of radiation and two thirds out of the field of radiation;with radiation, they develop two thirds of the second cancers in the fieldof radiation and one third out of the field of radiation. Because the cancersthat occur out of the field of radiation tend to occur at a later age, thosewho received radiation develop their cancers at a younger age overall and,therefore, have radiation-induced cancer deaths at an earlier age.15,16 In fact, in the United States, themain cause of death in RB patients is not RB—it is their second, nonocular,cancer!17 The overall risk of radiation-inducedsecond cancers is about 1% per year, which is higher than that of any othercured pediatric malignancy.18

The knowledge of radiation-related second cancers has been one of themain stimuli for the development of alternative strategies in the managementand treatment of patients with RB. Worldwide, systemic and local chemotherapieshave been used since the mid-1990s in the hope that cures for RB may be attainedwithout an increased risk of second cancers.1922 Chemotherapyalone seems to rarely cure intraocular RB; however, when combined with focaltechniques (photocoagulation, transpupillary thermotherapy, cryotherapy, andradioactive plaques), it has proved to be a useful adjunct, often obviatingthe need for EBT. The success of the chemotherapy plus focal techniques approach,however, seems related to the extent of the intraocular disease. For Reese-Ellsworth(RE) groups I, II, and III, radiation can usually be avoided. For eyes inwhich the tumors are larger, such as RE groups IV (multiple tumors, some >10disc diameters, and/or lesions extending anteriorly to the ora serrata) andV (massive tumors involving more than half of the retina, with or withoutseeding), success rates are much lower. These children require multidrug chemotherapy,usually for 6 to 9 months, with a significant incidence of systemic toxicity,including anemia, anorexia, leukopenia, myelosuppression, neurotoxicity, neutropenia,secondary infections, and optic atrophy.23 Theliterature20,21,24 suggeststhat most of these eyes are not cured with chemotherapy alone and may stillreceive EBT and/or undergo enucleation. The impact of a chemotherapeutic approachon second cancers is not known, but recent evidence2529 suggeststhat acute myelocytic leukemia may be induced by etoposide.

The question of deciding between multiagent chemotherapy or EBT foradvanced disease would seem to be a simple weighing in of the known risksand benefits of each approach. With the many articles on radiation, it wouldseem that the success rates and complications for eyes with advanced diseaseare known and well published; however, when we reviewed the literature, wewere surprised to find that there are no articles exclusively focusing onradiation for eyes with RE group Vb RB. In some series, these cases are includedin the overall reports, but it is impossible to filter out exactly how oftenradiated group Vb eyes are cured, require subsequent enucleation, developnew intraocular tumor foci, have complications, and develop second cancers,and what the final visual outcome is for this important subset. We believethat modern-day clinicians could not make a fair and balanced decision aboutchemotherapy as an initial choice for eyes with group Vb RB without this information;consequently, we undertook a study to answer these questions. We limited thisseries to cases performed in recent times with modern dosing, fractionation,and portals; therefore, we did not include those cases treated previouslyby Algernon B. Reese, MD.3035

A retrospective medical record review was conducted for all patientswho were examined by us between January 1, 1979, and February 28, 2002, atthe Robert M. Ellsworth Ophthalmic Oncology Center, New York, NY, and whoinitially had at least one eye diagnosed as having RE group Vb RB. A diagnosisof RB was defined as the presence of 1 or more retinal tumors detected onfunduscopic examination using indirect ophthalmoscopy and scleral depression.The following clinical data were collected: sex, family history, age at diagnosis,laterality, and initial treatment modality for the group Vb eye (enucleation,EBT, or other).

For those who received EBT as the initial treatment for the RE groupVb eyes, the following clinical data were collected: age of RE group Vb eyeat initial treatment, EBT variables, development of recurrent or new oculartumors, ocular complication rate following EBT, whether additional treatmentwas given following initial EBT, development of additional primary neoplasms,length of follow-up, and visual acuity following EBT. Radiation therapy wasadministered in a fairly consistent fashion during this period. The dose prescribedto the retinal target volume ranged from 4200 to 4600 rad (4200-4600 cGy).The children were treated 5 days per week, with fractions of 180 to 200 rad/d(180-200 cGy/d).

Ocular survival was evaluated for RE group Vb eyes that received radiationas their initial treatment during the follow-up period from the date of diagnosis.For ocular survival analysis, the event variable was enucleation.

Patient survival was also evaluated during the follow-up period fromthe date of diagnosis for the following cohorts: all patients with RB diagnosedas having at least one RE group Vb eye, patients with bilateral RB with atleast one RE group Vb eye, patients with unilateral RB with one RE group Vbeye, patients with bilateral RB with at least one RE group Vb eye treatedwith EBT, patients with bilateral RB with at least one RE group Vb eye treatedinitially with EBT, and patients with bilateral RB with at least one RE groupVb eye who were never treated with EBT.

Probability curves for the development of a second nonocular cancerwere generated for the following subgroups of patients with bilateral diseasewho received EBT as the initial treatment for the group Vb eyes: all 43 patientsfrom the date of diagnosis to the development of a second primary neoplasmor the date of the last follow-up for those who did not develop a second cancer,those who were diagnosed as having the disease at 12 months or younger vsolder than 12 months during the follow-up period from the date of diagnosis,and those who were diagnosed as having the disease at 12 months or youngervs older than 12 months during the follow-up period of 5 years from the datethat EBT was initiated.

We used the Kaplan-Meier method for incidence and survival analysis.Survival comparisons were made using the log-rank test with a 5% significancelevel. All statistics were calculated using computer software (WinSTAT add-infor Microsoft Excel version 2000.1; R. Fitch Software, Cambridge, Mass). Tobe consistent with our prior publications, trilateral RBs (pineoblastomas)were classified as second nonocular neoplasms.

The study was approved by the Weill Medical College of Cornell UniversityInstitutional Review Board (under protocol 0403-777).

DEMOGRAPHICS

Two hundred forty-three patients were identified as having at leastone RE group Vb eye at diagnosis, with a mean follow-up of 5 years (median,3.5 years; range, <1-20.3 years). There were 284 group Vb eyes among these243 patients. Patient characteristics are listed in Table 1.

Table Graphic Jump LocationTable 1. Demographic Variables for the 243 Patients
INITIAL TREATMENT MODALITIES

Sixty-three (22.2%) of the 284 group Vb eyes, representing 53 patients(43 with bilateral RB and 10 with unilateral RB), were initially treated withEBT. The median age at initial treatment with EBT of the RE group Vb eye was14 months (range, 1-53 months). Twenty-seven (50.9%) of these patients were1 year or younger at the time of EBT, while 26 (49.1%) were older than 1 year.One hundred seventy-two (60.6%) of the group Vb eyes, representing 170 patients,were treated with initial enucleation. The median age of the RE group Vb eyesinitially enucleated was 23 months (range, 1-154 months). Forty-nine (17.3%)of the group Vb eyes, representing 33 patients, were treated with anotherinitial treatment modality. Information regarding the initial treatment ofthe RE group Vb eyes is listed in Table2.

Table Graphic Jump LocationTable 2. Initial Treatment Modality of 284 RE Group Vb Eyes in 243Patients With Retinoblastoma
OCULAR OUTCOMES FOLLOWING EBT
Disease Status

Of the 63 group Vb eyes initially treated with EBT, 26 developed recurrenceof intraocular RB, 8 developed a new intraocular tumor, and 2 developed recurrenceand a new intraocular tumor. Thirty-one of the RE group Vb eyes initiallytreated with EBT developed no intraocular disease recurrence or new tumors. Table 3 lists the variables associatedwith ocular outcome.

Table Graphic Jump LocationTable 3. Ocular Outcome Following EBT in 63 Eyes
Ocular Complications

The overall ocular complication rate following EBT for a group Vb eyewas 52.4%, with 33 of 63 eyes developing a total of 41 ocular complications.The types of complications observed are summarized in Table 3.

Ocular Survival

Table 3 summarizes the survivalfor the group Vb eyes that were treated initially with EBT. Of the 63 groupVb eyes initially treated with EBT, 25 were eventually enucleated while 38survived to the last follow-up. Twenty-one (55.3%) of the 38 eyes that survivedto the last follow-up required no additional treatment after EBT, while 17(44.7%) required some type of salvage treatment. The 25 group Vb eyesthat were eventually enucleated had a median survival of 14 months (range,5-107 months) after treatment, while the 38 group Vb eyes that survived tothe last follow-up had a median survival of 112 months (range, 3-228 months). Figure 1 demonstrates the Kaplan-Meier curvefor ocular survival for all group Vb eyes treated with initial EBT. Survivaltime (81.4% at 1 year, 56.4% at 5 years, and 53.4% at 10 years) is measuredfrom the end of EBT to the date of enucleation or last follow-up.

Place holder to copy figure label and caption
Figure 1.

Kaplan-Meier curve for the ocularsurvival of 63 group Vb eyes initially treated with external beam radiotherapy(EBT). Survival time is measured from the end of the EBT treatment periodto the date of either enucleation or last follow-up.

Graphic Jump Location
Visual Acuity

Visual acuity information was available for 28 of the 38 eyes that survivedto the last follow-up (Table 4).Of these 38 eyes, 17 (44.7%) required additional treatment and 21 (55.3%)required no additional treatment. These data represent the most recent visualacuity that was recorded for each patient. Eight eyes (21.1%) had a visualacuity of at least 20/50. No eye had a visual acuity of 20/20 following EBT.Eyes that required no additional treatment following EBT had slightly bettervisual acuities (9 [42.9%] of 21 with a visual acuity ≥20/200) than eyesthat required additional treatment (6 [35.3%] of 17 with a visual acuity ≥20/200).

Table Graphic Jump LocationTable 4. Visual Acuity of 38 RE Group Vb Eyes That Received EBT asthe Initial Treatment and Survived to the Last Follow-up
DEVELOPMENT OF NONOCULAR TUMORS

Thirteen (5.3%) of the 243 group Vb patients developed second nonoculartumors. Of these 13 patients, 12 had bilateral RB. One patient had unilateralRB (group Vb disease), but was first seen with a pineoblastoma and had a positivefamily history of RB. Ten patients (76.9%) received EBT as their initial therapy,while the remaining 3 (23.1%) received EBT as salvage treatment. The typesof second nonocular cancers are listed in Table 5. Of 13 secondary neoplasms, 11 occurred in the field ofradiation. The cumulative probability of a patient with bilateral RB developinga second nonocular cancer following initial EBT for an RE group Vb eye isshown in Figure 2: at 1 year afterdiagnosis, the probability is 2.3%; at 5 years, 11.2%; and at 10 years, 29.7%.If the Kaplan-Meier curves for the probability of developing a second nonocularcancer following EBT to an RE group Vb eye in a patient with bilateral diseaseare compared between those receiving initial EBT at 1 year or younger andthose receiving initial EBT at older than 1 year, the difference is not significant(P = .49 and P>.05, respectively).Even if the comparison between the curves is defined as the first 60 monthsfollowing EBT, the probability of developing a second nonocular cancer isnot significantly different between these 2 groups (P =.09 and P>.05, respectively). Overall, 7 patientswith bilateral RB died of a second nonocular cancer; 6 of these patients receivedradiation as initial treatment for 1 or more eyes with RE group Vb disease. Figure 3 is a Kaplan-Meier curve demonstrating,for the patients with bilateral RB diagnosed as having at least one RE groupVb eye and who received EBT as the initial treatment, freedom from the developmentof second cancers for 93.6% at 5 years and 10 years after diagnosis and 52.6%at 18¼ years after diagnosis.

Table Graphic Jump LocationTable 5. Second Nonocular Tumor Development in 13 Patients Diagnosedas Having 1 or More RE Group Vb Eyes
Place holder to copy figure label and caption
Figure 2.

Incidence of developing a secondnonocular cancer in the 43 patients with bilateral retinoblastoma (RB) withat least one group Vb eye treated with initial external beam radiotherapy.Time is measured from the date of diagnosis of RB to the date of diagnosisof the second cancer or the date of last follow-up for those patients whodid not develop a second cancer.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Event-free incidence followinginitial external beam radiotherapy for group Vb retinoblastoma (RB). Deathsdue to metastatic RB in patients with unilateral and bilateral disease areincluded, as are deaths due to second nonocular cancers in patients with bilateralRB.

Graphic Jump Location
PATIENT SURVIVAL

Of the 243 group Vb patients, there were 13 confirmed deaths: 6 of metastaticdisease and 7 of second cancers. Figure 3 shows freedom from metastatic disease for patients with unilateraland bilateral RB diagnosed as having at least one RE group Vb eye. One patientwith unilateral RB and no known family history of RB died of metastatic disease15 months after diagnosis. The group Vb eye was treated initially by enucleation.The rate of freedom from the development of metastatic RB for patients withbilateral disease with 1 or more RE group Vb eye was 99.0% at 1 year afterdiagnosis and 93.3% at 5 and 90.3% at 10 years after diagnosis. Of the 5 patientswith bilateral disease who died of metastatic RB, 3 (3 of 43 total patients)received radiation as the initial treatment for the group Vb eye. Two patientsdied following initial enucleation for the group Vb eye and recurrence followingfailed EBT for the other (non–group Vb) eye. The median (mean ±SD) age at death for all 13 patients who died was 8.1 (8.0 ± 4.8) years,while the median (mean ± SD) age at death for the 9 patients who diedand received initial EBT was 6.2 (8.1 ± 5.7) years.

The RE RB classification system is not, nor was it intended to be, atraditional cancer staging scheme. In traditional cancer schemes, the untreatedcancer progresses from a lower stage to a higher stage. This progression mayeven occur despite treatment. The RE classification system was designed toallow clinicians worldwide to compare the results of lateral photon externalbeam therapy for RB. The features that most predicted failure with this techniquewere tumor location and size and the presence of vitreous seeds.36 Themore anterior a tumor, the lower the success rate; and the larger the tumor,the lower the success rate with lateral photons. Thus, group V describes tumorsinvolving more than half the retina, while group I tumors are 0 to 4 discdiameters behind the equator. A review of all subsequent articles4,5,7,8,31,32,3747 revealsthe strength of this scheme; every center has found that group V tumors areless often cured with radiation than group I, II, III, and IV tumors. In NewYork, 85% of RE groups I through III avoided enucleation after primary EBT.48

Reese-Ellsworth group Vb represents cases with vitreous seeds. Theywere classified as group V because most, but not all, of the cases with vitreousseeds were associated with large retinal tumors. Group Vb represented thehardest to cure because focal techniques failed and the subsequent alternativeswere global treatments: enucleation or EBT. Deciphering exactly how hard theseeyes were to cure with radiation has been confusing: many researchers frequentlylumped together group IV and V eyes in their analyses4 orreported their experience with group V eyes alone (ie, not subdividing caseswith seeds vs large tumors). Cassady et al31 reporteda 20% cure rate for groups IV and V. McCormick et al46 reporteda 35% cure rate for groups IV and V, Foote et al43 reportedcontrol in 2 of 10 cases, and Egbert et al44 reportedsuccess in only 29% of group IV and V eyes. It was previously reported that42% of group IV and V (together) eyes survived with the anterior lens-sparingtechnique,49 and 50% were controlled with themodified lateral beam technique after EBT.5 Indescribing his experience with only RE group V eyes, Stallard37 reportedthat treatment failed in 11 of his 20 group V eyes treated between 1948 and1960. Cassady et al reported that only 15% of group V eyes were locally controlled.Egbert et al reported failure in 12 of 14 cases. Foote et al reported no successes.Fontanesi et al8 reported success in only 1of 4 cases. In the largest cohort of group V eyes described in the UnitedStates, 38% of the irradiated eyes avoided enucleation.49

Few published reports focus exclusively on the success or failure ofradiation for group Vb eyes. In one report from China, 5 of 6 irradiated eyeswere in patients with group Vb disease. Two eyes were saved. One had a visualacuity of 20/30 and the other had peripheral vision.50 Amongthe landmark radiation articles that have not subdivided group Vb eyes arethose of Stallard,37 Abramson et al,48,49 Blach et al,5 Hernandezet al,4 Fontanesi et al,8 Cassadyet al,31 Bedford et al,40 Merchantet al,6 and Amendola et al.7 Thus,we believed that the paucity of data on group Vb eyes justified this analysisof our experience with radiation for group Vb eyes. To our knowledge, ourseries of 53 patients who underwent radiation, with 63 group Vb eyes, representsthe largest in the literature. Some of our findings were expected, while otherswere not.

Of the 284 eyes classified as RE group Vb at our institution betweenJanuary 1, 1979, and February 28, 2002, 172 were enucleated primarily. Althoughwe did not have a protocol in effect to determine which group Vb eyes wereto be enucleated primarily, most of them were in patients with unilateraldisease and/or in patients who had rubeosis, painful blind eyes, or buphthalmosor who were believed by us to have no reasonable hope of vision. While thelatter category is "soft," it is important to realize that when comparingradiation with chemotherapy, the initial selection of which eyes to enucleatemay significantly affect success/failure rates with chemotherapy or radiation.

As expected, there were an equal number of boys and girls affected withgroup Vb eyes and, overall, 90.1% of newly diagnosed cases had no family historyof RB. Also expected was the observation that the median age at diagnosiswas younger for the patients with bilateral disease (10 months) than for thepatients with unilateral disease (26 months) diagnosed as having group Vbeyes, and that most group Vb eyes receiving initial EBT were in patients withbilateral disease (n = 43), with 10 patients with unilateral disease initiallytreated with EBT. It has been previously noted that EBT for patients withunilateral disease is possible, with success, but great care must be takenin choosing such patients.10 The risks andbenefits must be clearly understood by the family and all treating physicians.

The ocular outcome variables we chose to analyze following initial EBTfor RE group Vb disease included ocular survival, disease recurrence, newtumor growth, visual acuity, and ocular complication rate. The ocular survivalfor all radiated group Vb eyes was 81.4% at 1 year, 56.4% at 5 years, and53.4% at 10 years. Failures following radiation usually occur in the firstor second year after treatment, and late failures following EBT of group Vbeyes are rare and usually reflect complications of treatment.

Approximately half (49.2%) of all group Vb eyes initially treated withEBT had no recurrence and no new tumors after a single course of EBT: of 63eyes, 26 (41.3%) developed recurrent disease and 8 (12.7%) developed new tumorfoci after radiation. Two eyes (3.2%) developed recurrence and new tumors.The subsequent development of new tumor foci in patients who underwent radiationhas been extensively reviewed elsewhere, and is directly related to the ageat which children are treated.47

Ocular complications following initial EBT were common, observable in52.4% of the group Vb eyes. As expected, the most common ocular complicationwas a cataract. Radiation retinopathy developed in only 1 patient, and vitreoushemorrhage, in 13 eyes. One striking observation of this study is that vitreoushemorrhage seems to be more common than generally appreciated following irradiation.

The visual results of group Vb eyes initially treated with EBT are oftenan important measure of success for the treating physicians and the family.Thirty-eight group Vb eyes, in patients who survived to the last follow-up,had useful data: 15 (39.5%) had a visual acuity of 20/200 or better, and 8(21.1%) had a visual acuity of 20/50 or better.

Our analysis of patient survival revealed that deaths due to metastaticdisease were uncommon in the patient populations with unilateral and bilateralRB. Of the 243 patients with 284 group Vb eyes, 137 were diagnosed as havingunilateral RB and had the unilateral diseased eye classified as RE group Vb.One hundred nineteen patients with unilateral disease had their group Vb eyetreated by primary enucleation. One patient developed metastasis and died15 months after enucleation. This patient had choroidal, optic nerve, andscleral invasion, and developed an orbital recurrence. Ten eyes in 10 patientswith unilateral disease were initially treated by EBT; no metastatic eventsoccurred.

In the patient population with bilateral disease with at least one groupVb eye (n = 106), 5 patients died of metastatic disease: 3 received bilateralradiation for bilateral group Vb disease as their initial treatment and 2underwent enucleation for the unilateral group Vb eye and radiation for theother, non–group Vb, eye as the primary treatment regimen. Both patientsdeveloped an orbital recurrence in the non–group Vb eye. No patientwith a group Vb eye that was treated with only primary enucleation (for unilateraldisease, or both eyes for bilateral disease) developed metastatic disease;3 patients with bilateral group Vb disease underwent bilateral enucleationas their initial treatment, with no metastatic events occurring.

The use of radiation for group Vb disease was not associated with thedevelopment of second nonocular cancers in our study in patients with sporadicunilateral RB. No patient with sporadic unilateral disease, whether undergoingenucleation or radiation, developed a second nonocular cancer. Prior studies18 have emphasized that patients with unilateral diseasewho harbor the germinal mutation are at risk of developing second nonocularcancers whether they receive radiation or not. It would seem that radiationfor eyes with unilateral group Vb disease in patients who do not harbor themutation is a reasonable treatment strategy for the management of RB.

Second tumor incidence in patients with bilateral disease is usuallythought to develop at 1% a year, so our observed incidence of 11.2% by 5 yearsand 29.7% by 10 years in this study seemed high. Because certain featureshave been demonstrated to further increase the incidence of second cancers,such as higher doses of radiation (a dose-response curve exists for sarcomas18), radiation in the first year of life, and the presenceof lipomas, we looked for these markers in our patient population. On furtheranalysis, our apparent increase above the previously reported incidence inpatients with bilateral disease following radiation is not attributable tothe following: (1) the age of the patient at EBT, (2) the laterality (totalsurface area) of the radiation, and (3) the dose of radiation. The childrenin our study were all treated at one institution with similar doses, so radiationdose is not the answer. Patients with bilateral disease could be bilaterallyaffected with group Vb disease or unilaterally affected with group Vb disease(and the other eye may have some other RE grouping). A detailed analysis ofpatients with bilateral disease treated with radiation in one or both eyesfailed to reveal a significant difference in second cancers. Last, 27 patientswith bilateral disease underwent radiation in the first 12 months of life,and 26 underwent radiation after the age of 1 year. A χ2 comparisonbetween the 2 probability curves when the time measured is adjusted from thedate of radiation revealed P = .09. While it is possiblethat some of this effect is due to age, the small numbers make it impossibleto be certain.

Furthermore, when we looked at all patients with bilateral RB and groupVb disease who received any radiation throughout their treatment course (n= 84), we found a 5.7% second cancer incidence by 5 years and a 26.3% incidenceby 11 years (data not shown). Those patients with bilateral group Vb diseasewho never received EBT (n = 22) developed no second cancers during the studyfollow-up period (data not shown). The difference between these 2 curves wasnot significant (P = .16 and P>.05, respectively). Perhaps our observed trend toward more secondcancers may reflect a real difference, but the numbers are small and the follow-upis short. Or, it is possible that we may be observing the earlier radiation-inducedsecond cancers rather than the later cancers known to develop in all survivorsof bilateral RB following radiation. Regardless, our study suggests that thepresence of vitreous seeds, in combination with EBT, is not a marker for anincreased risk of second cancers.

External beam radiation as an initial treatment for selected cases ofRE group Vb eyes is associated with few metastatic disease cases and deathsfrom RB. Most eyes can be salvaged (81.4% at 1 year and 53.4% at 10 years)with vision; yet, ocular complications are common, with vitreous hemorrhagesoccurring more often than generally appreciated following EBT.

A comparative study looking at the use of chemotherapy as the initialtreatment for management of RE group Vb disease is necessary. Like the radiationdata for group Vb eyes, few published reports focus exclusively on the successor failure of chemotherapy for group Vb eyes: groups IV and V are analyzedtogether as advanced disease5154 orgroup V eyes are described with references to vitreous seed response.20,21,5558 Chemotherapyfor intraocular RB is still in its infancy, with dosing, agent selection,and response variables yet to be optimized; therefore, long-term consistenttreatment data and follow-up data, with particular attention to local controland complication rates (ocular and systemic), are unavailable. We look forwardto these future studies, which will enable clinicians to make informed risk-benefitassessments for patients with group Vb disease.

Correspondence: David H. Abramson, MD, Department of Ophthalmology,New York Presbyterian Hospital–Weill Medical College of Cornell University,70 E 66th St, New York, NY 10021 (dhamd@aol.com).

Submitted for publication August 14, 2003; final revision received January16, 2004; accepted March 4, 2004.

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Abramson  DHEllsworth  RMKitchin  FDTung  G Second nonocular tumors in retinoblastoma survivors: are they radiationinduced? Ophthalmology. 1984;911351- 1355
PubMed Link to Article
Wong  FLBoice  JDAbramson  DH  et al.  Cancer incidence after retinoblastoma. JAMA. 1997;2781262- 1267
PubMed Link to Article
Abramson  DHFrank  CM Second nonocular tumors in survivors of bilateral retinoblastoma: apossible age effect on radiation-related risk. Ophthalmology. 1998;105573- 580
PubMed Link to Article
Moll  ACImhof  SMSchouten–Van Meeteren  AYNKuik  DJBoers  M Second primary tumors in hereditary retinoblastoma: a register-basedstudy, 1945-1997. Ophthalmology. 2001;1081109- 1114
PubMed Link to Article
Desjardins  LHaye  CSchlienger  PLaurent  MZucker  JMBouguila  H Second non-ocular tumours in survivors of bilateral retinoblastoma:a 30-year follow-up. Ophthalmic Paediatr Genet. 1991;12145- 148
PubMed Link to Article
Abramson  DHEllsworth  RMZimmerman  LE Nonocular cancer in retinoblastoma survivors. Trans Am Acad Ophthalmol Otolaryngol. 1976;81 (1) 454- 457
PubMed
Abramson  DHDunkel  IMcCormick  BM Neoplasms of the eye. Holland  JedCancer Medicine. 4th Baltimore, Md Williams & Wilkins1996;1517- 1536
Eng  CLi  FPAbramson  DH  et al.  Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst. 1993;851121- 1128
PubMed Link to Article
Gallie  BLBudning  ADeBoer  G  et al.  Chemotherapy with focal therapy can cure intraocular retinoblastomawithout radiotherapy. Arch Ophthalmol. 1986;1141321- 1328
PubMed Link to Article
Shields  CLDePotter  PHimelstein  BPShield  JAMeadows  AT Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol. 1996;1141330- 1338
PubMed Link to Article
Kingston  JEHungerford  JLMadreperla  SAPlowman  PN Results of combined chemotherapy and radiotherapy for advanced intraocularretinoblastoma. Arch Ophthalmol. 1996;1141339- 1347
PubMed Link to Article
Murphree  ALVillablanca  JGDeegan  WF  III  et al.  Chemotherapy plus local treatment in the management of intraocularretinoblastoma. Arch Ophthalmol. 1996;1141348- 1356
PubMed Link to Article
Moss  RW The grand illusion of chemotherapy. Dtsch Z Onkol. 2001;3315- 18
Link to Article
Finger  PTCzechonska  GDemirci  HRausen  A Chemotherapy for retinoblastoma: a current topic. Drugs. 1999;58983- 996
PubMed Link to Article
Gallegos-Castorena  SMedina-Sanson  AGonzalez-Montalvo  PMartinez-Avalos  AZafra de la Rosa  GZ Letter to the editor: acute myeloid leukemia in a patient survivingretinoblastoma. Med Pediatr Oncol. 2002;38- 450
PubMed
Nishimura  SSato  TUeda  HUeda  K Acute myeloblastic leukemia as a second malignancy in a patient withhereditary retinoblastoma. J Clin Oncol. 2001;194182- 4183
PubMed
Felice  MSZubizarreta  PAChantada  GL  et al.  Acute myeloid leukemia as a second malignancy: report of 9 pediatricpatients in a single institution in Argentina. Med Pediatr Oncol. 1998;30160- 164
PubMed Link to Article
Turner  ARMelynk  AClark  G MDS and acute monocytic leukemia after retinoblastoma [letter]. Br J Haematol. 1996;92- 249
PubMed
White  LOrtega  JAYing  KL Acute non-lymphocytic leukemia following multimodality therapy forretinoblastoma. Cancer. 1985;55496- 498
PubMed Link to Article
Reese  AB Tumors of the Eye. 3rd New York, NY Harper & Row1976;
Cassady  JRSagerman  RHTrettor  PEllsworth  RM Radiation therapy in retinoblastoma: an analysis of 230 cases. Radiology. 1969;93405409;
PubMed
Ellsworth  RM The practical management of retinoblastoma. Trans Am Ophthalmol Soc. 1969;67462- 534
PubMed
Reese  ABEllsworth  RM The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol Otolaryngol. 1963;67164- 172
PubMed
Reese  ABHyman  GATapley  NDForrest  AW The treatment of retinoblastoma by x-ray and triethylene melamine. Arch Ophthalmol. 1958;60897- 906
Link to Article
Reese  ABMerriam  GRMartin  HE Treatment of bilateral retinoblastoma by irradiation and surgery: reporton 15-year results. Am J Ophthalmol. 1949;32175- 190
Abramson  DHJereb  BEllsworth  RM External beam radiation for retinoblastoma. Bull N Y Acad Med. 1981;57787- 803
PubMed
Stallard  HB The treatment of retinoblastoma. Bibl Ophthalmol. 1968;75149- 173
PubMed
Lennox  ELDraper  GJSanders  BM Retinoblastoma: a study of natural history and prognosis of 268 cases. BMJ. 1975;3731- 734
PubMed Link to Article
Haye  CDesjardins  LElmaleh  CSchlienger  PZucker  JMLaurent  M Prognosis and treatment of retinoblastoma: 105 cases treated at InstitutCurie. Ophthalmic Paediatr Genet. 1989;10151- 155
PubMed Link to Article
Bedford  MABedotto  CMacfaul  PA Retinoblastoma: a study of 139 cases. Br J Ophthalmol. 1971;5519- 27
PubMed Link to Article
Schipper  JTan  KEvan Peperzeel  HA Treatment of retinoblastoma by precision megavolt radiation therapy. Radiother Oncol. 1985;3117- 132
PubMed Link to Article
Thompson  RWSmall  RCStein  JJ Treatment of retinoblastoma. Am J Roentgenol Radium Ther Nucl Med. 1972;11416- 23
PubMed
Foote  RLGarretson  BRSchomberg  PJBuskirk  SJRobertson  DMEarle  JD External beam irradiation for retinoblastoma: patterns of failure anddose-response analysis. Int J Radiat Oncol Biol Phys. 1989;16823- 830
PubMed Link to Article
Egbert  PRDonaldson  SSMoazed  KRosenthal  R Visual results and ocular complications following radiotherapy forretinoblastoma. Arch Ophthalmol. 1978;961826- 1830
PubMed Link to Article
Gagnon  JOWare  CMMoss  WTStevens  KR Radiation management of bilateral retinoblastoma: the need to preservevision. Int J Radiat Oncol Biol Phys. 1980;6669- 673
PubMed Link to Article
McCormick  BEllsworth  RAbramson  DLoSasso  TGrabowski  E Results of external beam radiation for children with retinoblastoma:a comparison of two techniques. J Pediatr Ophthalmol Strabismus. 1989;26239- 243
PubMed
Abramson  DH Treatment of retinoblastoma. Blodi  FCedRetinoblastoma (ContemporaryIssues in Ophthalmology). New York, NY Churchhill Livingstone Inc1985;3- 93
Abramson  DHEllsworth  RMTretter  PJavitt  JKitchin  FD Treatment of bilateral groups I through III retinoblastoma with bilateralradiation. Arch Ophthalmol. 1981;991761- 1762
PubMed Link to Article
Abramson  DHEllsworth  RMTretter  PAdams  KKitchin  FD Simultaneous bilateral radiation for advanced bilateral retinoblastoma. Arch Ophthalmol. 1981;991763- 1766
PubMed Link to Article
Kao  LYTsang  NM Advanced bilateral retinoblastoma treated conservatively with lenssparing external beam radiation therapy: report of three cases. Changgeng Yi Xue Za Zhi. 1999;22100- 105
PubMed
Sussman  DAEscalona-Benz  EBenz  MS  et al.  Comparison of retinoblastoma reduction for chemotherapy vs externalbeam radiotherapy. Arch Ophthalmol. 2003;121979- 984
PubMed Link to Article
Wilson  MWRodriguez-Galindo  CHaik  BGMoshfeghi  DMMerchant  TEPratt  CB Multiagent chemotherapy as neoadjuvant treatment for multifocal intraocularretinoblastoma. Ophthalmology. 2001;1082106- 2115
PubMed Link to Article
Rodriguez-Galindo  CWilson  MWHaik  BG  et al.  Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol. 2003;212019- 2025
PubMed Link to Article
Beck  MNBalmer  ADessing  CPica  AMunier  F First-line chemotherapy with local treatment can prevent external-beamirradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol. 2000;182881- 2887
PubMed
Gunduz  KShields  CLShields  JA  et al.  The outcome of chemoreduction treatment in patients with Reese-Ellsworthgroup V retinoblastoma. Arch Ophthalmol. 1998;1161613- 1617
PubMed Link to Article
Shields  CLHonavar  SGMeadows  AT  et al.  Chemoreduction plus focal therapy for retinoblastoma: factors predictiveof need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol. 2002;133657- 664
PubMed Link to Article
Shields  CLHonavar  SGMeadows  ATShields  JADemirci  HNaduvilah  TJ Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol. 2002;1201653- 1658
PubMed Link to Article
Brichard  BDe Bruycker  JJDe Potter  PNeven  BVermylen  CCornu  G Combined chemotherapy and local treatment in the management of intraocularretinoblastoma. Med Pediatr Oncol. 2002;38411- 415
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Kaplan-Meier curve for the ocularsurvival of 63 group Vb eyes initially treated with external beam radiotherapy(EBT). Survival time is measured from the end of the EBT treatment periodto the date of either enucleation or last follow-up.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Incidence of developing a secondnonocular cancer in the 43 patients with bilateral retinoblastoma (RB) withat least one group Vb eye treated with initial external beam radiotherapy.Time is measured from the date of diagnosis of RB to the date of diagnosisof the second cancer or the date of last follow-up for those patients whodid not develop a second cancer.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Event-free incidence followinginitial external beam radiotherapy for group Vb retinoblastoma (RB). Deathsdue to metastatic RB in patients with unilateral and bilateral disease areincluded, as are deaths due to second nonocular cancers in patients with bilateralRB.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic Variables for the 243 Patients
Table Graphic Jump LocationTable 2. Initial Treatment Modality of 284 RE Group Vb Eyes in 243Patients With Retinoblastoma
Table Graphic Jump LocationTable 3. Ocular Outcome Following EBT in 63 Eyes
Table Graphic Jump LocationTable 4. Visual Acuity of 38 RE Group Vb Eyes That Received EBT asthe Initial Treatment and Survived to the Last Follow-up
Table Graphic Jump LocationTable 5. Second Nonocular Tumor Development in 13 Patients Diagnosedas Having 1 or More RE Group Vb Eyes

References

Hilgartner  HL Report of a case of double glioma treated by x-rays. Texas Med J. 1903;18322- 323
Servodidio  CAAbramson  DH Acute and long-term effects of radiation therapy to the eye in children. Cancer Nurs. 1993;16371- 381
PubMed Link to Article
Reese  AB Retinoblastoma. Tumors of the Eye. 2nd New York,NY Harper & Row1963;84- 157
Hernandez  JCBrady  LWShields  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;35125- 132
PubMed Link to Article
Blach  LEMcCormick  BAbramson  DH External beam radiation therapy and retinoblastoma: long-term resultsin the comparison of two techniques. Int J Radiat Oncol Biol Phys. 1996;3545- 51
PubMed Link to Article
Merchant  TEGould  CJHilton  NE  et al.  Ocular preservation after 36 Gy external beam radiation therapy forretinoblastoma. J Pediatr Hematol Oncol. 2002;24246- 249
PubMed Link to Article
Amendola  BELamm  FRMarkoe  AM  et al.  Radiotherapy of retinoblastoma: a review of 63 children treated withdifferent irradiation techniques. Cancer. 1990;6621- 26
PubMed Link to Article
Fontanesi  JPratt  CBHustu  HOCoffey  DKun  LEMeyer  D Use of irradiation for therapy of retinoblastoma in children more than1 year old: the St. Jude Children's Research Hospital experience and reviewof literature. Med Pediatr Oncol. 1995;24321- 326
PubMed Link to Article
Imhof  SMMourits  MPHofman  P  et al.  Quantification of orbital and mid-facial growth retardation after megavoltageexternal beam irradiation in children with retinoblastoma. Ophthalmology. 1996;103263- 268
PubMed Link to Article
Abramson  DHMarks  RFEllsworth  RMTretter  PKitchin  FD The management of unilateral retinoblastoma without primary enucleation. Arch Ophthalmol. 1982;1001249- 1252
PubMed Link to Article
Abramson  DHEllsworth  RMKitchin  FDTung  G Second nonocular tumors in retinoblastoma survivors: are they radiationinduced? Ophthalmology. 1984;911351- 1355
PubMed Link to Article
Wong  FLBoice  JDAbramson  DH  et al.  Cancer incidence after retinoblastoma. JAMA. 1997;2781262- 1267
PubMed Link to Article
Abramson  DHFrank  CM Second nonocular tumors in survivors of bilateral retinoblastoma: apossible age effect on radiation-related risk. Ophthalmology. 1998;105573- 580
PubMed Link to Article
Moll  ACImhof  SMSchouten–Van Meeteren  AYNKuik  DJBoers  M Second primary tumors in hereditary retinoblastoma: a register-basedstudy, 1945-1997. Ophthalmology. 2001;1081109- 1114
PubMed Link to Article
Desjardins  LHaye  CSchlienger  PLaurent  MZucker  JMBouguila  H Second non-ocular tumours in survivors of bilateral retinoblastoma:a 30-year follow-up. Ophthalmic Paediatr Genet. 1991;12145- 148
PubMed Link to Article
Abramson  DHEllsworth  RMZimmerman  LE Nonocular cancer in retinoblastoma survivors. Trans Am Acad Ophthalmol Otolaryngol. 1976;81 (1) 454- 457
PubMed
Abramson  DHDunkel  IMcCormick  BM Neoplasms of the eye. Holland  JedCancer Medicine. 4th Baltimore, Md Williams & Wilkins1996;1517- 1536
Eng  CLi  FPAbramson  DH  et al.  Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst. 1993;851121- 1128
PubMed Link to Article
Gallie  BLBudning  ADeBoer  G  et al.  Chemotherapy with focal therapy can cure intraocular retinoblastomawithout radiotherapy. Arch Ophthalmol. 1986;1141321- 1328
PubMed Link to Article
Shields  CLDePotter  PHimelstein  BPShield  JAMeadows  AT Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol. 1996;1141330- 1338
PubMed Link to Article
Kingston  JEHungerford  JLMadreperla  SAPlowman  PN Results of combined chemotherapy and radiotherapy for advanced intraocularretinoblastoma. Arch Ophthalmol. 1996;1141339- 1347
PubMed Link to Article
Murphree  ALVillablanca  JGDeegan  WF  III  et al.  Chemotherapy plus local treatment in the management of intraocularretinoblastoma. Arch Ophthalmol. 1996;1141348- 1356
PubMed Link to Article
Moss  RW The grand illusion of chemotherapy. Dtsch Z Onkol. 2001;3315- 18
Link to Article
Finger  PTCzechonska  GDemirci  HRausen  A Chemotherapy for retinoblastoma: a current topic. Drugs. 1999;58983- 996
PubMed Link to Article
Gallegos-Castorena  SMedina-Sanson  AGonzalez-Montalvo  PMartinez-Avalos  AZafra de la Rosa  GZ Letter to the editor: acute myeloid leukemia in a patient survivingretinoblastoma. Med Pediatr Oncol. 2002;38- 450
PubMed
Nishimura  SSato  TUeda  HUeda  K Acute myeloblastic leukemia as a second malignancy in a patient withhereditary retinoblastoma. J Clin Oncol. 2001;194182- 4183
PubMed
Felice  MSZubizarreta  PAChantada  GL  et al.  Acute myeloid leukemia as a second malignancy: report of 9 pediatricpatients in a single institution in Argentina. Med Pediatr Oncol. 1998;30160- 164
PubMed Link to Article
Turner  ARMelynk  AClark  G MDS and acute monocytic leukemia after retinoblastoma [letter]. Br J Haematol. 1996;92- 249
PubMed
White  LOrtega  JAYing  KL Acute non-lymphocytic leukemia following multimodality therapy forretinoblastoma. Cancer. 1985;55496- 498
PubMed Link to Article
Reese  AB Tumors of the Eye. 3rd New York, NY Harper & Row1976;
Cassady  JRSagerman  RHTrettor  PEllsworth  RM Radiation therapy in retinoblastoma: an analysis of 230 cases. Radiology. 1969;93405409;
PubMed
Ellsworth  RM The practical management of retinoblastoma. Trans Am Ophthalmol Soc. 1969;67462- 534
PubMed
Reese  ABEllsworth  RM The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol Otolaryngol. 1963;67164- 172
PubMed
Reese  ABHyman  GATapley  NDForrest  AW The treatment of retinoblastoma by x-ray and triethylene melamine. Arch Ophthalmol. 1958;60897- 906
Link to Article
Reese  ABMerriam  GRMartin  HE Treatment of bilateral retinoblastoma by irradiation and surgery: reporton 15-year results. Am J Ophthalmol. 1949;32175- 190
Abramson  DHJereb  BEllsworth  RM External beam radiation for retinoblastoma. Bull N Y Acad Med. 1981;57787- 803
PubMed
Stallard  HB The treatment of retinoblastoma. Bibl Ophthalmol. 1968;75149- 173
PubMed
Lennox  ELDraper  GJSanders  BM Retinoblastoma: a study of natural history and prognosis of 268 cases. BMJ. 1975;3731- 734
PubMed Link to Article
Haye  CDesjardins  LElmaleh  CSchlienger  PZucker  JMLaurent  M Prognosis and treatment of retinoblastoma: 105 cases treated at InstitutCurie. Ophthalmic Paediatr Genet. 1989;10151- 155
PubMed Link to Article
Bedford  MABedotto  CMacfaul  PA Retinoblastoma: a study of 139 cases. Br J Ophthalmol. 1971;5519- 27
PubMed Link to Article
Schipper  JTan  KEvan Peperzeel  HA Treatment of retinoblastoma by precision megavolt radiation therapy. Radiother Oncol. 1985;3117- 132
PubMed Link to Article
Thompson  RWSmall  RCStein  JJ Treatment of retinoblastoma. Am J Roentgenol Radium Ther Nucl Med. 1972;11416- 23
PubMed
Foote  RLGarretson  BRSchomberg  PJBuskirk  SJRobertson  DMEarle  JD External beam irradiation for retinoblastoma: patterns of failure anddose-response analysis. Int J Radiat Oncol Biol Phys. 1989;16823- 830
PubMed Link to Article
Egbert  PRDonaldson  SSMoazed  KRosenthal  R Visual results and ocular complications following radiotherapy forretinoblastoma. Arch Ophthalmol. 1978;961826- 1830
PubMed Link to Article
Gagnon  JOWare  CMMoss  WTStevens  KR Radiation management of bilateral retinoblastoma: the need to preservevision. Int J Radiat Oncol Biol Phys. 1980;6669- 673
PubMed Link to Article
McCormick  BEllsworth  RAbramson  DLoSasso  TGrabowski  E Results of external beam radiation for children with retinoblastoma:a comparison of two techniques. J Pediatr Ophthalmol Strabismus. 1989;26239- 243
PubMed
Abramson  DH Treatment of retinoblastoma. Blodi  FCedRetinoblastoma (ContemporaryIssues in Ophthalmology). New York, NY Churchhill Livingstone Inc1985;3- 93
Abramson  DHEllsworth  RMTretter  PJavitt  JKitchin  FD Treatment of bilateral groups I through III retinoblastoma with bilateralradiation. Arch Ophthalmol. 1981;991761- 1762
PubMed Link to Article
Abramson  DHEllsworth  RMTretter  PAdams  KKitchin  FD Simultaneous bilateral radiation for advanced bilateral retinoblastoma. Arch Ophthalmol. 1981;991763- 1766
PubMed Link to Article
Kao  LYTsang  NM Advanced bilateral retinoblastoma treated conservatively with lenssparing external beam radiation therapy: report of three cases. Changgeng Yi Xue Za Zhi. 1999;22100- 105
PubMed
Sussman  DAEscalona-Benz  EBenz  MS  et al.  Comparison of retinoblastoma reduction for chemotherapy vs externalbeam radiotherapy. Arch Ophthalmol. 2003;121979- 984
PubMed Link to Article
Wilson  MWRodriguez-Galindo  CHaik  BGMoshfeghi  DMMerchant  TEPratt  CB Multiagent chemotherapy as neoadjuvant treatment for multifocal intraocularretinoblastoma. Ophthalmology. 2001;1082106- 2115
PubMed Link to Article
Rodriguez-Galindo  CWilson  MWHaik  BG  et al.  Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol. 2003;212019- 2025
PubMed Link to Article
Beck  MNBalmer  ADessing  CPica  AMunier  F First-line chemotherapy with local treatment can prevent external-beamirradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol. 2000;182881- 2887
PubMed
Gunduz  KShields  CLShields  JA  et al.  The outcome of chemoreduction treatment in patients with Reese-Ellsworthgroup V retinoblastoma. Arch Ophthalmol. 1998;1161613- 1617
PubMed Link to Article
Shields  CLHonavar  SGMeadows  AT  et al.  Chemoreduction plus focal therapy for retinoblastoma: factors predictiveof need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol. 2002;133657- 664
PubMed Link to Article
Shields  CLHonavar  SGMeadows  ATShields  JADemirci  HNaduvilah  TJ Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol. 2002;1201653- 1658
PubMed Link to Article
Brichard  BDe Bruycker  JJDe Potter  PNeven  BVermylen  CCornu  G Combined chemotherapy and local treatment in the management of intraocularretinoblastoma. Med Pediatr Oncol. 2002;38411- 415
PubMed Link to Article

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