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	�:	External Beam Radiation Therapy for Retinoblastoma Resistant to Chemotherapy and Focal Treatment: Outcome and Predictive Factors.
Yacoub A. Yousef, M.D,1 Imad Mahameed, M.D, 1 Mustafa Mehyar, M.D, 1 Rasha Barham, M.D, 1 Khalil Alrawashdeh, M.D, 1 Iyad Sultan.MD,2 Ibrahim Nawaiseh.MD, 1 Imad Jaradat, Ph.D.3

Departments of Surgery, 1 Pediatrics,2 and Radiotherapy.3 King Hussein Cancer Center, Amman, Jordan.
Abbreviated title: EBRT for RB Resistant to Chemotherapy.
Correspondence to:  Imad Jaradat. PhD 
Address: King Hussein Cancer Center, Department of Surgery
              Queen Rania AlAbdullah Street, P.O Box 1269, 
              Amman 11941, Jordan

Conflict of interest: none
Financial Disclosure:  None.

World count: 2311.

Abstract
Purpose: To evaluate the outcome of external beam radiation therapy (EBRT) for treatment of retinoblastoma resistant to chemotherapy and focal therapy.
Methods and Materials: A retrospective case series of 24 eyes for 20 retinoblastoma patients treated by EBRT after failure of tumor control by chemotherapy and focal therapy. The main outcome measures included: international intraocular retinoblastoma stage (IIRC) and Reese Ellsworth (RE) stage, tumor seeding, treatment modalities, eye salvage, and survival.
Results: The median age at diagnosis was 12 months. There were 12(60%) males and 16(80%) bilateral cases. All eyes were treated initially by systemic chemotherapy (range; 6-8 cycles). The dose of 45Gy was used in all eyes. 
Eye salvage rate after EBRT was 45%(11eyes). The mean follow-up was 55months; 67%( 2/3) for IIRC group B, 63 %(5/8) for group C, and 31%(4/13) for group D eyes. Vitreous seeds and tumor stage migration during management by chemotherapy were the most important significant predictive factors for tumor control (p= 0.0327 and 0.0333 consecutively). 
Conclusion: Eyes with retinoblastoma that failed chemotherapy were controlled with EBRT. However the presence of vitreous seeds, stage migration during chemotherapy, as well as good vision in the other eye may not justify the known risks of EBRT.
Introduction
Retinoblastoma is the most common primary intraocular malignancy in childhood and infancy. The incidence is estimated at about 1 in 15,000 to 20,000 live births. 1, 2
In 1954, external beam radiotherapy (EBRT) emerged as the first eye salvage therapy for advanced intraocular retinoblastoma, and was used extensively as primary treatment.3 Although EBRT was often effective to control tumor growth, it was associated with ocular complications; and therefore enucleation following radiation was more often because of these complications than because of the treatment�s failure to control the tumors. Moreover, EBRT greatly increased the lifelong risk of second cancers in children with a germline RB1 gene mutation, and was associated with cosmetic problems due to orbital bone growth retardation, particularly in younger patients.4,5  Therefore, systemic chemotherapy combined with focal therapy became the primary treatment for intraocular retinoblastoma in the 1990s,6  and achieved high globe salvage rates (100% for International Intraocular Retinoblastoma Classification (IIRC) Group A, 93% for group B, 90% for Group C and 47% for Group D eyes).7
Despite the use of new treatment options, such as photocoagulation, 8 cryotherapy, 9 plaque therapy, 10 and thermochemotherapy11 with good success rates, EBRT (mainly with the new advances in types and techniques of radiation) still one of the most effective therapies for resistant cases for chemotherapy in situations where globe salvage is desired, particularly when the opposite eye is enucleated.19- 22  
Herein we are evaluating the outcome and the factors affecting the outcome of using EBRT in management of resistant intraocular retinoblastoma cases that failed treatment by combined chemotherapy and focal therapy.
Methods
This study was approved by the institutional review board. It was a retrospective case series of 24 eyes for 20 consecutive patients who had clinical diagnosis of intraocular retinoblastoma and treated with EBRT after failure of tumor control by combined chemotherapy and focal therapy. Selection required access to patients� medical records, and Ret-Cam images. 
Data included patient�s age, gender, laterality, age at diagnosis, initial IIRC stage, 12 initial Reese-Ellsworth (RE) group, 13 type of seeds (subretinal and vitreal), focal therapy, dose of radiation therapy, post radiation complications, eye salvage, visual acuity, metastasis, second malignancy, and mortality. 
Inclusion and Exclusion criteria:
The eligibility criteria for inclusion were children with intraocular retinoblastoma (as the presence of one or more retinal tumors detected on funduscopic examination using indirect ophthalmoscopy and scleral depression) who were initially treated with chemotherapy and focal treatment; however, these patients showed no response to these modalities since the beginning or showed favorable response initially but developed recurrence of the tumor during or after the treatment. Treatment was therefore followed by EBRT. Exclusion criteria included eyes that received plaque radiation therapy before EBRT, and eyes followed for less than 12 months (unless there was recurrence). 
Clinical Characteristics and definitions
Tumors were staged at presentation according to IIRC12 and RE13 staging systems. At time of radiation, tumors were divided into three groups; 1. No tumor seeds, 2. Subretinal seeds, and 3. Vitreal seeds. Stage migration was defined as tumor progression and development of new clinical features during management (by chemotherapy and focal therapy) that are features of more advanced IIRC stage than the initial tumor stage at time of diagnosis. Failure of tumor control by combined chemotherapy and focal therapy was defined as tumor or seeds recurrence with the need for External Beam Radiation therapy or enucleation. Eye salvage was defined as tumor control and avoidance of enucleation. The decision for enucleation was approved by two ocular oncologists and after consultation of an external reviewer.
Treatment Methods
We performed a combination regimen of chemotherapy that consisted of CVE (carboplatin, etoposide, and vincristine). Every CVE cycle was repeated every 4 weeks for a total of 6 to 8 cycles according to patient�s condition and tumor status. Ocular oncology follow-up was provided with examination under anesthesia before every cycle of chemotherapy and every 4 to 8 weeks thereafter. Fundus photos were taken using a RetCam II (Clarity Medical System, Pleasanton, CA, USA), and focal therapy was provided using thermotherapy or cryotherapy until tumor control was achieved. 
Radiation therapy was administered in a consistent fashion. Simulation and treatment were done for patients under general anesthesia while wearing a thermoplastic head mask immobilization device. All patients were treated in supine position using a linear accelerator at a photon energy of 6 MV (Elekta -synergy) through a three dimensional conformal radiotherapy. The dose prescribed to the retinal target volume was 45 Gy in 25 fractions of 1.8 Gy.
Statistical Analysis
Statistical analysis of tumor control and eye salvage were correlated to the gender, laterality, IIRC group, RE stage, type of seeds, stage migration, number of chemotherapy cycles, and dose of radiation. The P value was measured using the exact Fisher test to test the predictive power of each factor.Results:
Between January 2003 and December 2012, there were 24 eyes for 20 patients with intraocular retinoblastoma (IIRC groups B, C, or D) resistant to treatment with combined chemotherapy and focal therapy and thereafter treated by EBRT. 
Demographics
The mean age at diagnosis was 20 months (median, 12 months; range, 2�48 months). There were 12 males (60%) and 8 females (40%). There were 4 (20%) unilateral and 16 (80%) bilateral cases. All unilateral cases and bilateral cases with good visual potential and tumor control in the other eye in this series refused the offered enucleation, therefore treated by EBRT. Patient�s demographics are listed in (Table 1). 
Treatment Modalities
All cases received systemic chemotherapy (CVE) with mean 7 cycles (median, 8 cycles; range, 6-8 cycles), and 8 (40%) patients were further treated by 3 cycles of subtenon carboplatin injections. Consolidation therapy was applied as post chemo-reduction transpupillary thermotherapy, cryotherapy, or both in each case. All treated eyes received the standard dose of 45Gy in 25 fractions of 1.8 GY. 
Ocular outcome
Eleven eyes (45%) salvaged by EBRT. The mean follow-up was 55 months (median, 42 months; range, 12-140 months) after radiation therapy. Eye salvage rate was 67% (2/3) for group B eyes, 63% (5/8) for group C eyes, and 31% (4/13) for group D eyes (Figure 1). 
Of the 11 eyes salvaged by EBRT, 3 eyes developed recurrence of intraocular RB after initial control for at least 3 months and 1 developed a new intraocular tumor, all of which were controlled by focal therapy (thermal therapy and/or cryotherapy).
Indication for enucleation in the 13 failed eyes were persistent tumor activity in 69% (9/13) of eyes, total retinal detachment (RD) and vitreous hemorrhage in 23% (3/13) of treated eyes, and neovascular glaucoma in 8% (1/13) of treated eye.
The overall ocular complication rate was 80% (19/24) of treated eyes; controllable tumor recurrence or new tumor (4), uncontrollable residual tumor (9), retinal detachment (3), vitreous hemorrhage (4), neovascular glaucoma (1), cataract (16), radiation retinopathy (2), and eventually enucleated (13).   
Visual acuity in the salvaged 11 eyes was better than 20/100 in 0 (0%), 20/100 to 20/200 in 3 (36%), 20/200 to 20/400 in 3 (27%), counting fingers to 20/400 in 3 (27%), light perception in 1 (10%), and no light perception in 1 (10%). Post-enucleation high-risk features were seen in 3 eyes, all were treated by adjuvant chemotherapy. One patient died secondary to bone marrow metastasis.  No single case of second malignancy was seen yet during the follow up period (mean 55 months, range 6-140 months).
Predictive Factors of Ocular outcome
Patient�s gender, tumor site, laterality, number of cycles of chemotherapy, and tumor stage at diagnosis did not show difference in the control rate of tumors treated by EBRT after failure of chemotherapy and focal therapy (Table 2). Of note, all the 4 unilateral cases in this series were consecutively enucleated; 3 had uncontrolled vitreous seeds and one had subretinal seeds and had massive hemorrhage post EBRT. 
Vitreous seeds at time of EBRT was associated with significantly higher risk of failure of tumor control (p= 0.03). Eye salvage was achieved in 67% (2/3) of eyes with no seeds, 71% (5/7) of eyes with retinal seeds, and only in 29% (4/14) of eyes with vitreous seeds. Stage migration was associated with significantly higher risk of failure of tumor control (p= 0.03). In our series stage migration was seen in 4 eyes (1 B eye and 3 C eyes), all showed IIRC group D features at time of radiation therapy, and all were not controlled by EBRT (Figure 2), meanwhile all the 6 eyes in groups B and C that did not show stage migration were controlled by EBRT. The initial RE stage was not predictive of the outcome in this series (p=1.0).

 

Discussion
 EBRT was the treatment of choice for retinoblastoma over many years, but because of radiation side effects, chemotherapy and focal therapy became the primary treatment of choice for retinoblastoma in most of the developed countries worldwide.3-7 Even though EBRT still in use after failure of chemotherapy combined with focal therapy.
Our series showed that the significant predictors for failure of EBRT for treatment of intraocular retinoblastoma after failure of chemotherapy and focal therapy were vitreous seeds as the indication for EBRT, and tumor stage migration during treatment by chemotherapy.  Failure of tumor control was not correlated to patient�s gender, tumor site, laterality, and number of cycles of chemotherapy. The initial RE stage was not predictive factor of the outcome as well.
The adverse effects associated with EBRT are major issues. Radiation is associated with 36%-51% risk of second cancers in heritable retinoblastoma that increases with patient�s age, which is more than three times the risk in non-irradiated heritable retinoblastoma patients. 14, 15 EBRT is associated with ocular complications including cataracts, blinding and painful anterior segment complications, vitreous hemorrhage, and orbital deformities.16 Herein we tried to highlight the predictive factors of tumor control by EBRT for retinoblastoma that was resistant to chemotherapy and focal therapy to determine whether the expected outcome justifies the risk of EBRT.
The overall ocular salvage rate for eyes with retinoblastoma treated initially by EBRT with no previous chemotherapy was 72% to 81%, 18-20 while ocular salvage rate in our series was 45%. Our lower salvage rate may be due to more tumor resistance in eyes that failed chemotherapy than eyes that were treated initially by EBRT, or due to the more advanced cases in our series where 55% of our cases where group Vb. Chan et al17 studied the rate of eye salvage by EBRT after failure of chemotherapy and focal therapy in 36 eyes, and reported 83.3% rate of eye salvage; range from 29% and 33% for groups Va and IIIa consecutively to 100% for groups I and II. Our success rate was 45%, ranging from 33% for goup Vb to 100% for group I, which still less than Chan�s salvage rate. Our relatively low overall success rate was due to the more advanced tumors in our series and therefore less favourable outcome. In fact, 50% of our patients were group Vb (the most advanced stage) and only 12.5% were groups I to III; while only 11% were group Vb and 55% were groups I to III in Chan�s series.
Few reports focused on the salvage rate by radiation therapy as initial treatment for group Vb eyes.16, 21,22 Abramson et al.16 described 63 group Vb eyes treated initially by EBRT, and the ocular survival rate was 53.4% at 10 years that still higher than our 33% control rate for the same group. That difference indicates that tumors uncontrolled by chemotherapy are the tumors that are originally highly resistant, and therefore were more resistant for EBRT than tumors that were treated initially by EBRT with no history of previous therapy. 
Even the RE13 RB classification system was not intended to be a traditional cancer staging scheme initially.16 Most reports revealed the strength of this scheme; and found that group V tumors are less often cured with radiation as initial therapy.23-26 In our series, the initial RE stage was not significant predictive factor for the tumor control rate in eyes failed chemotherapy (p=1.00). That was expected as some eyes showed features of more advanced tumor stage during management process as vitreous seeds, which may not correlate with the initial tumor stage. Vitreous seeds at time of radiation therapy was associated with un-favorable tumor control (p= 0.03). Off note, the initial staging was not predictive of the outcome of management by EBRT, while tumor deterioration and development of more advanced tumor features during chemotherapy (stage migration) was significant poor predictive factor for tumor control (p= 0.03). 
Chan et al17 concluded that salvage EBRT was highly effective in preserving eyes with useful vision in bilateral retinoblastoma after failed chemotherapy and focal treatments without evaluating the predictive factors of the outcome. Our study highlighted the poor outcome of eyes that had vitreous seeds and/or tumor stage migration before EBRT, and showed that patient�s gender, tumor site, laterality, and number of cycles of chemotherapy, were not significantly associated with difference in the control rate of tumors treated. 
In conclusion, our results show that eyes with retinoblastoma treated by EBRT after failure of chemotherapy may be more resistant than eyes treated initially by EBRT. Even it has a role to salvage eyes with no vitreous seeds (mainly when there is good visual potential), EBRT has low ocular salvage rate for eyes with vitreous seeds and eyes that deteriorated during chemotherapy, and therefore the radiation side effects may not be justified for this group mainly if the other eye is either normal or has good vision and tumor control.
This study examined the outcome and the predictive factors for tumor control by EBRT for retinoblastoma eyes that was resistant to chemotherapy and focal therapy.  Although this is unique work, it is retrospective and of limited size. Therefore, a larger and more comprehensive multicenter study should be performed to analyze better the efficacy and tumor-specific factors to expect the outcome of radiation therapy, and to justify the possible associated risks.
References
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Figure Legend:
Figure 1: Clinical images of an eye with intraocular retinoblastoma (in a patient who had the left eye enucleated for advanced intraocular retinoblastoma) that was salvaged by EBRT after failure of combined chemotherapy and focal therapy.
Fundus exam of the right eye at diagnosis showed intraocular retinal tumor with total retinal detachment (A+B). After 6 cycles of CVE chemotherapy combined with transpupillary thermotherapy and cryotherapy, the tumor responded by shrinkage and calcifications (C+D). Residual active tumors were not controlled at 2 different quadrants; inferotemporal (E) and superonasal (F) after additional 3 sessions of focal treatment by triple freeze thaw cryotherapy, therefore EBRT was applied. No tumor activity was seen over 2 years follow up post salvage EBRT (G+H). 
Figure 2: Clinical images of an eye with intraocular retinoblastoma (in a patient who had bilateral retinoblastoma) that showed stage migration during chemotherapy and focal therapy, and consequentially failed treatment by EBRT.
Fundus exam of the left eye at diagnosis showed 2 retinal tumors (A+B) with no subretinal or vitreous seeds (staged as IIRC group B). After 6 cycles of CVE chemotherapy combined with transpupillary thermotherapy and cryotherapy, the tumors responded partially by shrinkage, scaring, and calcifications but showed stage migration where new vitreous seeds (features of IIRC group D tumor) appeared (C+D) that are features of more advanced tumor than the initial presentation. Since the vitreous seeds were not controlled by additional 2 cycles of CVE and 3 cycles of subtenon carboplatin injections, salvage EBRT was applied. Initially the tumor was controlled by EBRT (E+F), but at 6 months post radiation, the main tumor around the optic disc could not be assessed well secondary to cataract (G), and tumor recurrence was seen close to the oral in the inferotemoral quadrant (H). Since cataract surgery was unsafe for the risk of metastasis, and the tumor in the other eye was well controlled with good visual potential, the eye was enucleated. Pathologicaly no high risk features were seen in the enucleated eye.    










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