Comparison of Retinoblastoma Reduction for Chemotherapy Vs External Beam Radiotherapy

CLINICAL SCIENCES Comparison of Retinoblastoma Reduction for Chemotherapy vs External Beam Radiotherapy

Daniel A. Sussman, MD; Erika Escalona-Benz, MD; Matthew S. Benz, MD; Brandy C. Hayden, BS; William Feuer, MS; Nicole Cicciarelli; Stuart Toledano, MD; Arnold Markoe, MD; Timothy G. Murray, MD

Objective: To determine the time course and extent of Results: Twenty-six eyes of 26 patients were evaluated tumor reduction associated with systemic chemo- for tumor response; 18 patients were treated with sys- therapy or external beam radiotherapy (EBRT) in the treat- temic chemotherapy and 8 patients were treated with ment of advanced intraocular retinoblastoma. EBRT. Median follow-up was 36 months. A mean 68% reduction in tumor volume occurred after 1 cycle of che- Methods: Retrospective review of children with Reese- motherapy compared with a 12% reduction at a similar Ellsworth stages IV and V retinoblastoma undergoing pri- time point (1 month) after initiation of EBRT (PϽ.004). mary globe-conserving therapy with either systemic che- There was no statistically significant difference in tu- moreduction or EBRT. Study variables were recorded at mor volume reduction between treatment modalities at baseline, at monthly intervals for the first 6 months, and the 12-month follow-up visit. Both systemic chemore- at 12 months after the initiation of treatment. Tumor vol- duction and EBRT achieved 100% globe conservation and umes were calculated using basal area and height values 100% patient survival in this series. determined by ultrasonography, physical examination, and fundus photographic review. Conclusions: Retinoblastoma reduction exhibits a differential time course based on the applied primary treat- Main Outcome Measures: Outcome measures in- ment. Systemic chemotherapy is associated with earlier cluded tumor volume, tumor reduction, regression pat- tumor reduction than EBRT. tern, treatment-related complications, metastases, and survival. Arch Ophthalmol. 2003;121:979-984

IMELY DIAGNOSIS and treat- as late as 30 years after primary treatment of intraocular retino- ment, but these malignancies may be- blastoma have contributed come less frequent in those patients un- to a marked improvement dergoing EBRT after 12 months of age.12-19 in patient survival.1,2 Re- These potential complications have led cently,T clinical advances have focused on many clinicians to shift their primary treat- intraocular tumor control enabling in- ment from EBRT toward systemic chemo- creased globe conservation while mini- therapy.4 Systemic chemotherapy has mizing the risk to the child.1-5 In addition proven to be an excellent tool in the treat- to enucleation, available treatments in- ment of retinoblastoma; however, it is not clude cryotherapy, laser ablation, chemo- exempt from complications including my- therapy, scleral plaque radiotherapy, elosuppression leading to neutropenia, From the Bascom Palmer Eye transpupillary thermoablation, external thrombocytopenia, or anemia requiring Institute (Drs Sussman, beam radiotherapy (EBRT), and com- unplanned hospital admissions.6,20-23 The Escalona-Benz, Benz, and bined therapeutic modalities.6,7 External present study compares the rate of regres- Murray, Mss Hayden and beam radiotherapy offers the potential of sion of Reese-Ellsworth stages IV and V Cicciarelli, and Mr Feuer), globe and sight preservation but has sig- retinoblastomas (ie, multiple tumors, some and the Divisions of Pediatric nificant limitations. This treatment mo- larger than 10 disc diameters, and any le- Hematology and Oncology dality has been associated with severe com- sion extending anterior to the ora serrata (Dr Toledano) and Radiation Oncology (Dr Markoe), plications such as cataracts, retinopathy, [stage IV] and massive tumors involving University of Miami School of vasculopathy, facial deformities, and op- more than half the retina [stage Va] and 6,8-11 Medicine, Miami, Fla. The tic neuropathy. In addition, up to 35% vitreous seeding (stage Vb) following pri- authors have no relevant of children with retinoblastoma treated mary therapy with systemic chemo- financial interest in this article. with EBRT develop a second malignancy therapy compared with EBRT.

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Those Who Those Who Type of Those Who Those Who Received Received P Adjunctive Received Received Variable Chemotherapy EBRT Total Value Therapy Chemotherapy EBRT Total Age, mean (SD), mo 9 (11) 17 (15) 11 (12) .16 None 0 2 (25) 2 (8) Male 11 (61) 6 (75) 17 (65) .67 Diode laser 9 (50) 1 (13) 10 (39) Race Cryotherapy 0 2 (25) 2 (8) White 9 (50) 6 (75) 15 (58) Diode laser + cryotherapy 9 (50) 3 (38) 12 (46) Black 3 (17) 1 (13) 4 (15) .64 Hispanic 5 (28) 1 (13) 6 (23) Abbreviation: EBRT, external beam radiotherapy. Other 1 (6) 0 1 (4) *Data are given as the number (percentage) of patients. Bilateral disease 14 (78) 7 (88) 21 (81) .99 Positive family history 8 (44) 0 8 (31) .03 All patients in the chemoreduction arm of the study re- R-E stage Vb† 8 (44) 5 (63) 13 (50) .67 ceived carboplatin (20 mg/kg for patients younger than 12 months; 550-600 mg/m2 body surface area for patients older than 12 Abbreviations: EBRT, external beam radiotherapy; R-E, Reese-Ellsworth. months), etoposide phosphate (5 mg/kg if the patient was younger *Data are given as the number (percentage) of patients unless otherwise 2 indicated. than 12 months; 150 mg/m body surface area if the patient was †The R-E stage Vb is vitreous seeding. older than 12 months), and vincristine sulfate (0.05 mg/kg if the patient was younger than 12 months; 1.5-2 mg/m2 body surface area if the patient was older than 12 months). For patients also receiving cyclosporine, cyclosporine was administered as a 5 Table 2. Primary Therapy mg/kg per hour bolus for 2 hours before chemotherapy started, then a 1.5 mg/kg per hour infusion during the next 30 hours if No. (%) the patient weighed less than 12 kg. These doses were ad- Type of Treatment of Patients justed to 4 mg/kg per hour and 1.25 mg/kg per hour, respec- Chemotherapy tively, if the patient weighed between 12 and 30 kg, or 3 mg/kg Carboplatin, etoposide phosphate, 18 (100) per hour and 1 mg/kg per hour, respectively, if the patient and vincristine sulfate weighed more than 30 kg.20 External beam radiotherapy was Cyclosporine 9 (50) administered using the relative lens-sparing technique and in- EBRT dose, rad (Gy) cluded treatment to the 95% isodose line, with a goal dose of 4320 (43.2) 1 (12) 4500 rad (45 Gy) of megavoltage radiation at 180 rad (1.8 Gy) 4500 (45.0) 7 (88) per fraction.5

Abbreviation: EBRT, external beam radiotherapy. CALCULATION OF TUMOR VOLUME

METHODS Echographic analysis was performed using an ultrasonic scan- ner (model I3; Innovative Imaging Inc, Sacramento, Calif) or The study protocol was approved by the institutional review the Alcon Ophthoscan-S or the Mini A Systems (Alcon Surgi- board of the University of Miami School of Medicine, Miami, cal, Irvine, Calif). Baseline echographic measurements of all tu- Fla. A retrospective review was performed of medical, photo- mors were obtained while the patient was anesthetized at the graphic, and echographic records of all patients who com- initial examination. Measurement of the maximal tumor height pleted systemic chemotherapy or EBRT as primary treatment was determined from baseline B-scan sections. of retinoblastoma at the Bascom Palmer Eye Institute, Miami, Kowa photographs (Kowa Optimed Inc, Torrance, Calif) with complete documentation from October 1, 1991, to May and/or Retcam 120 images (Massie Research Laboratories Inc, 31, 2001. A total of 175 records was reviewed; 26 patients met Dublin, Calif), obtained at the initial presentation and at each the inclusion criteria of the study. Only patients with Reese- follow-up examination, were used for photographic analysis. Ellsworth stages IV and V retinoblastomas were included in the A digital montage of Kowa images was created using a slide scan- study. Reese-Ellsworth stages I, II, and III retinoblastomas were ner (model LS-2000; Nikon Corp, Tokyo, Japan) and photo- excluded from the study as focal therapies are preferred for pri- graphic montaging software (Sketcher 3.0; Ophthalmic Tech- mary treatment of these tumors at our institution. Patients ini- nologies Inc, Toronto, Ontario). Montage images displayed tially treated outside the Bascom Palmer Eye Institute and pa- borders of tumor and included images of the optic disc for ref- tients undergoing primary enucleation were excluded from the erence. Measurement of the tumor length, width, and basal area study. Those with incomplete or inadequate photographic and/or were determined from photographic analysis using caliper mea- echographic tumor documentation also were excluded from this surements and were internally validated using the optic disc study to allow accurate measurement of the tumor size. If more as a reference (1.5 mm in diameter). Tumor surface areas in than 1 tumor was present, only the largest tumor at baseline Retcam 120 images were obtained using the Retcam software was included in the study. Each patient underwent examina- that enabled us to calculate tumor surface area after outlining tion under anesthesia on presentation and at monthly inter- the margins of the tumor. vals during the follow-up period. Data collected included the Tumor volumes were calculated using radius, basal area, patient’s age at diagnosis, family history, Reese-Ellsworth stage and height values as determined by ultrasonographic, photo- at presentation, type of primary treatment (systemic chemo- graphic, and physical examination. The following formula was therapy or EBRT), number of cycles of treatment, total dose of used for the calculation of the tumor volume radiation, type of adjunctive therapy (laser and/or cryo- 1 2 Volume=( ⁄3ϫ␲ϫheight )ϫ(3ϫradius − height). therapy), calculation of the tumor volume, type of tumor regression pattern, recurrence of the tumor, preservation of the This formula allows increased accuracy in quantifying globe, and survival of the patient. intraocular tumor volumes.24

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D E F

Figure 1. A, Baseline view showing the retinoblastoma before systemic chemotherapy. B, View showing the retinoblastoma after 2 months of treatment with systemic chemotherapy. C, View showing the retinoblastoma after 12 months of treatment with systemic chemotherapy. D, Baseline view showing tumor before external beam radiotherapy (EBRT). E, View showing tumor after 2 months of treatment with EBRT. F, View showing tumor after 12 months of treatment with EBRT.

Percent change in tumor area and volume were cal- the cycles of systemic chemotherapy. In addition, 9 (50%) culated at 1-, 2-, 3-, 4-, 5-, 6-, and 12-month intervals. If of 18 patients received adjunctive cryotherapy during an a patient had multiple tumors, only the largest tumor was examination under anesthesia. Six of the 8 patients treated tracked for volume reduction. The accuracy of data was with EBRT received cryotherapy, transpupillary diode la- verified through evaluations by multiple investigators ser therapy, or both during an examination under anes- (E.E.B., M.S.B., and T.G.M.) who were masked to treat- thesia. Adjunctive treatment data are given in Table 3. ment modality. Patient survival was 100%, none of the patients developed metastases at the last follow-up, and there was a STATISTICAL ANALYSIS 100% globe conservation rate. There was a statistically significant difference in tu- Statistical significance was assessed using the Fisher exact test mor volume reduction between systemic chemotherapy ␹2 or the test for categorical variables and the 2-sample t test and EBRT at the first (PϽ.004) and second (PϽ.04) for continuous variables. months after the initiation of therapy (Figure 1). Pa- tients treated with systemic chemotherapy had a tumor RESULTS volume 32% of baseline (68% reduction from baseline) Twenty-six eyes of 26 patients with retinoblastomas were while those patients treated with EBRT had a tumor vol- evaluated. Seventeen patients (65%) were male; 9 pa- ume 88% of baseline (12% reduction from baseline) at tients (35%) were female. Bilateral tumors were present the first-month follow-up visit. The difference in rate of in 21 patients (81%); 8 patients (31%) had a positive fam- tumor volume reduction persisted but gradually de- ily history of retinoblastoma. Mean age at presentation creased until the 12-month follow-up visit, when the tu- was 11 months (age range, 6 days to 49 months). Eigh- mor volume reduction was noted to be similar between Figure 2). Data for tumor vol- teen patients (69%) received systemic chemotherapy; 8 the 2 groups (P=.76) ( ume changes are listed in Table 4. patients (31%) received EBRT. Mean follow-up was 35 Local treatment-related complications are given in months (follow-up range, 6-72 months). Thirteen pa- Table 5. Posterior subcapsular cataract was present in tients (50%) were initially seen with Reese-Ellsworth stage 7 of 26 patients, vitreous hemorrhage in 4 of 26 pa- Vb disease (ie, with vitreous seeding). Demographic data tients, and midfacial hypoplasia in 2 of 26 patients. Cata- are summarized in Table 1. Systemic chemotherapy with a combination of car- racts (7 of 8 patients) and midfacial hypoplasia (2 of 8 patients) developed exclusively in patients treated with boplatin, vincristine, and etoposide with or without cy- Ͻ Ͻ closporine was given every 3 weeks to a goal of 9 cycles EBRT (P .001 and P .09, respectively). There was no (mean, 7 cycles). Nine patients (50%) treated with sys- significant difference in any other local treatment- temic chemotherapy also received cyclosporine. Exter- related complication, including retinal vasculopathy and nal beam radiotherapy was delivered in a single daily optic neuropathy. fractionation over an approximate 3-week interval to a goal dose of 45 000 rad (450 Gy). Primary therapy data COMMENT are listed in Table 2. All of the patients treated with systemic chemo- Systemic chemotherapy and EBRT with adjunctive la- therapy (18 of 18 patients) received adjunctive transpu- ser, cryotherapy, or both are associated with significant pillary diode laser therapy applied at the time of exami- retinoblastoma volume reduction. In the current study, nation administered under anesthesia immediately before patients treated with primary systemic chemoreduction

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 120 Table 5. Local Treatment-Related Complications* Patients Who Received Systemic Chemotherapy 100 Those Who Patients Who Received External Beam Radiotherapy Received Those Who P Complication Chemotherapy Received EBRT Value 80 Vitreous hemorrhage 3 (17) 1 (13) .99 Vasculopathy 1 (6) 0 .99 60 Optic neuropathy 1 (6) 0 .99 Cataract 0 7 (88) Ͻ.001 40 Optic disc swelling 1 (6) 0 .99 Baseline Tumor Size, % Baseline Tumor Retinopathy 0 0 NA Midfacial hypoplasia 0 2 (25) .09 20 Abbreviations: EBRT, external beam radiotherapy; NA, not applicable. *Data are given as the number (percentage) of patients. 0 246810 12 Months documented to achieve tumor control through direct Figure 2. Greater change in tumor volume with systemic chemoreduction 27 compared with external beam radiotherapy. Note there is no difference at the tumoricidal effects. Radiotherapeutic effects though 12-month follow-up visit. may not be immediately apparent as cell death is initi- ated through DNA damage often not manifested until cell cycling. External beam radiotherapy has also been Table 4. Tumor Volumes During the 12 Months After associated with transient tumor enlargement with local Initiation of Treatment intratumoral edema.5 Globe-conservation rates in the present study were % of Baseline Volume, Mean (SD) 100% in both groups. This compares favorably with previously published results. Scott et al5 reported 91% globe Those Who Those Who Month of Received Received P conservation at 36 months using the relative lens- Follow-up Chemotherapy EBRT Value sparing technique of EBRT for patients with Reese- 28 1 32 (26) 88 (32) .004 Ellsworth stages I through Vb disease. Egbert et al re- 2 19 (15) 42 (32) .04 ported 29% ocular survival following therapy with lateral 3 16 (16) 25 (18) .40 beam EBRT on patients with Reese-Ellsworth stages IV 4 14 (18) 31 (19) .13 and V retinoblastomas with a follow-up range of 2.5 to 5 9 (14) 36 (NA) .09 21 years. Shields et al29 reported 100% and 78% ocular 6 8 (14) 23 (15) .20 salvage rates when a chemotherapeutic regimen consist- 12 9 (17) 6 (2) .76 ing of a combination of carboplatin, vincristine, and eto- Abbreviations: EBRT, external beam radiotherapy; NA, not applicable. poside with adjuvant treatment was used on stages IV and V retinoblastomas, respectively.29 In this study, the 100% globe-conservation rate was likely affected favorably by exhibited an earlier reduction of tumor volume than those the exclusion of patients undergoing primary enucle- treated with EBRT. ation. Furthermore, outcomes may have been favorably Early reduction in tumor size is vital to the success- influenced by the small sample size. ful treatment of retinoblastoma; reduction in tumor vol- In patients undergoing treatment with systemic che- ume allows for effective application of local treatments, moreduction or EBRT for retinoblastoma, adjuvant lo- leading to tumor control. Visual compromise depends on cal treatments with laser and cryotherapy are valuable in tumor size and extent of foveal involvement.25 Faster re- controlling tumor growth. Laser and cryotherapy play a duction in tumor volume and partial reduction in foveal role in speeding the rate of regression of these tumors. involvement may allow for improved visual acuity out- Our laboratory has previously reported that application comes and decreased amblyopia and strabismus given the of focal adjunctive therapies to retinoblastomas at the time plasticity of the pediatric visual system. of systemic chemotherapy dosing or radiation therapy in- In this study, calculations of change in volume be- creases the efficacy of the systemic chemoreductive agents tween consecutive follow-up examinations were based and allows for a reduction in total ocular and periocular on the change in tumor size as observed clinically and radiation dose while maintaining excellent local tumor in fundus photographs in addition to echographic mea- control in the murine model of retinoblastoma.30-32 It has surements. Char et al26 have demonstrated the relative been demonstrated that multiagent chemotherapy alone accuracy of such clinical estimations in assessing tumor does not ensure intraocular control for multifocal reti- dimensions when compared with more conventional mo- noblastoma. Thus, supplemental focal treatment may be dalities such as echography. needed to control disease progression.33 Focal ablative We postulate that direct laser ablation coupled therapies may cause complications including transient with concomitant systemic chemotherapy leads to a ablatio fugax, retinal vascular occlusion, retinal holes, pre- rapid direct tumor cell death, enhanced vascular clo- retinal fibrosis, and retinal traction and tears.23 In this sure, and a potential synergy of each individual modal- study, all patients receiving chemotherapy also received ity. External beam radiotherapy has been previously adjuvant therapy. Fifty percent of these patients re-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 ceived laser therapy; the remaining 50% were treated with toma volume so that the tumors will be amenable to lo- a combination of laser and cryotherapy. Two patients cal treatments with laser and cryotherapy. The time course treated with EBRT received no adjuvant treatment. The of tumor volume reduction and treatment-associated mor- small sample size of patients receiving no adjuvant treat- bidity of these newer, local primary therapies will need ment in this study precluded comparative analysis in out- to be compared with systemic chemotherapy to provide comes between patients receiving adjuvant treatments and optimum therapeutic intervention and to minimize ad- those not receiving adjuvant treatment. verse effects. An important goal in the treatment of retinoblastoma is to achieve local tumor control and globe conser- CONCLUSIONS vation while minimizing treatment-related morbidity. Ad- juvant therapies combined with primary treatment Retinoblastoma reduction exhibits a differential time modalities have achieved tumor control in human sub- course and extent based on the applied primary treat- jects.20,34-38 In low-risk patients with other neurologic tu- ment. Systemic chemotherapy is associated with earlier mors (eg, medulloblastoma), adjuvant chemotherapy al- tumor volume reduction than EBRT. Combined appli- lows for dose reduction of irradiation, which results in cation of multiple treatment modalities may enhance tu- improved quality of life and fewer radiation-related com- mor reduction and accelerate the time course of tumor plications.39 Further refinement of current therapies and response. development of new treatments for retinoblastoma should continue the trend toward combination therapy and al- Submitted for publication August 6, 2002; final revision re- low for dose reduction and minimization of treatment- ceived February 26, 2003; accepted March 11, 2003. related morbidity. Corresponding author and reprints: Timothy G. Mur- External beam radiotherapy can lead to significant ray, MD, Bascom Palmer Eye Institute, University of Mi- local adverse effects. In the present study, 7 (88%) of 8 ami School of Medicine, PO Box 016880, Miami, FL 33101 eyes treated with EBRT developed posterior subcapsu- (e-mail: [email protected]). lar cataracts; none of the chemotherapy-treated eyes developed cataracts. Two (25%)of 8 patients treated with REFERENCES EBRT developed midfacial hypoplasia, while none of the chemotherapy-treated patients developed facial abnor- 1. Char D. Clinical Ocular Oncology. New York, NY: Churchill Livingstone Inc; 1989: 207-224. malities. Treatment of retinoblastoma with systemic che- 2. Shields JA, Shields CL. Management and prognosis of retinoblastoma. In: Shields motherapy appears to be less likely to result in signifi- JA, Shields CL, eds. Intraocular Tumors: A Text and Atlas. Philadelphia, Pa: WB cant local adverse effects than treatment with EBRT. Saunders Co; 1992:377-392. Systemic complications of EBRT include late tumor 3. Abramson DH. Retinoblastoma: diagnosis and management. 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