Proton Radiation Therapy for the Treatment of Retinoblastoma

doi:10.1016/j.ijrobp.2014.07.031

International Journal of Radiation OncologyBiologyPhysics

Volume 90, Issue 4, 15 November 2014, Pages 863-869

Presented in part at the 55th Annual Meeting of the American Society for Radiation Oncology, September 22-25, 2013, Atlanta, GA.

https://doi.org/10.1016/j.ijrobp.2014.07.031 Get rights and content

Purpose

To investigate long-term disease and toxicity outcomes for pediatric retinoblastoma patients treated with proton radiation therapy (PRT).

Methods and Materials

This is a retrospective analysis of 49 retinoblastoma patients (60 eyes) treated with PRT between 1986 and 2012.

Results

The majority (84%) of patients had bilateral disease, and nearly half (45%) had received prior chemotherapy. At a median follow-up of 8 years (range, 1-24 years), no patients died of retinoblastoma or developed metastatic disease. The post-PRT enucleation rate was low (18%), especially in patients with early-stage disease (11% for patients with International Classification for Intraocular Retinoblastoma [ICIR] stage A-B disease vs 23% for patients with ICIR stage C-D disease). Post-PRT ophthalmologic follow-up was available for 61% of the preserved eyes (30 of 49): 14 of 30 eyes (47%) had 20/40 visual acuity or better, 7 of 30 (23%) had moderate visual acuity (20/40-20/600), and 9 of 30 (30%) had little or no useful vision (worse than 20/600). Twelve of 60 treated eyes (20%) experienced a post-PRT event requiring intervention, with cataracts the most common (4 eyes). No patients developed an in-field second malignancy.

Conclusions

Long-term follow-up of retinoblastoma patients treated with PRT demonstrates that PRT can achieve high local control rates, even in advanced cases, and many patients retain useful vision in the treated eye. Treatment-related ocular side effects were uncommon, and no radiation-associated malignancies were observed.

Introduction

Retinoblastoma is the most common intraocular malignancy of childhood, and nearly 300 new cases are diagnosed each year in the United States 1, 2. Approximately 60% of tumors are sporadic, whereas 40% are hereditary owing to germline loss or mutation of the RB1 tumor suppressor gene 2, 3. Sporadic cases of retinoblastoma are typically unilateral, whereas most patients with hereditary disease present with bilateral tumors. Although not uncommonly seen in developing countries, metastases are rare at diagnosis in North America; therefore, definitive management relies on effective treatment of the ocular tumor(s).

External beam radiation therapy (EBRT) has been used in the treatment of retinoblastoma for more than a century and was the preferred vision-sparing treatment approach for many years 4, 5, 6. Long-term eye preservation rates range from 50% to 100% in several large series, with outcomes better for early-stage versus advanced tumors 7, 8, 9. However, use of EBRT has decreased sharply over the past 2 decades owing to the advent of effective chemotherapeutic regimens as well as concern for radiation-induced side effects, including growth abnormalities and second malignancies 10, 11, 12, 13. Currently EBRT is typically reserved for cases of progressive or persistent disease after chemotherapy and focal treatment (cryotherapy or laser photocoagulation), or in advanced cases when vitreous or subretinal seeding is present 14, 15. Even in these advanced or refractory cases, ocular salvage and vision preservation can often be achieved 5, 7.

External beam radiation therapy techniques have evolved significantly over time, and conformal photon techniques and proton RT (PRT) are now favored for treatment of retinoblastoma 16, 17. Because of its unique physical properties and lack of exit dose, PRT minimizes normal tissue exposure and may be associated with lower rates of radiation-induced normal tissue injury and malignancies compared with contemporary photon-based techniques (18). Proton RT has been used in the treatment of retinoblastoma at our institution since 1986, and here we report the long-term outcomes of patients treated with this approach.

Section snippets

Patient population

We identified all patients who received PRT for retinoblastoma at our institution between 1986 and 2010 and who had at least 1 year of follow-up data available (4 patients excluded owing to inadequate follow-up). Patients with extraocular tumors or who had received previous radiation (EBRT or brachytherapy) were excluded from the analysis (n=5). Patients receiving PRT after enucleation were also excluded (n=3). For eligible patients, all available medical records were analyzed. This study was

Patient and treatment characteristics

A total of 49 patients and 60 irradiated eyes were included in the analysis (Table 1). Approximately half of the patients (26 of 49, 53%) were female. The median age at diagnosis was 6 months and ranged from 6 days to 30 months. Of the 49 patients, 29 (59%) presented with clinical signs of retinoblastoma. Leukocoria was the most common sign (18 of 29), followed by strabismus or head tilt (10 of 29). Approximately one-quarter of patients were diagnosed by screening (12 of 49), and these patients

Discussion

Here we report long-term outcomes of retinoblastoma patients treated with PRT. To our knowledge, this represents the largest and most mature experience available for this patient population.

For nearly a century, photon-based RT was the standard of care for retinoblastoma patients and was associated with high rates of disease control and vision preservation 4, 5, 7, 8, 9, 20. However, patients remained at significant risk for toxicities including growth abnormalities and radiation-induced

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A case of retinoblastoma resulting in phthisis bulbi after proton beam radiation therapy
2022, American Journal of Ophthalmology Case Reports
Citation Excerpt :
Compared with conventional photon-based radiotherapy, PBRT minimizes damage to normal adjacent structures18 and may potentially reduce the risk for long-term adverse events.16,19,20 Well-known PBRT-induced adverse events include cataracts, radiation retinopathy, neovascular glaucoma, optic neuropathy, and vitreous hemorrhage, though phthisis bulbi is rarely reported.18,21 To the best of our knowledge, only one case with ciliary body failure, which was highly similar to phthisis bulbi after PBRT, has been reported.4
Proton beam radiation therapy (PBRT) is a treatment option for advanced retinoblastoma (RB) resistant to chemotherapy and focal ophthalmic treatment. Here we report a case of RB with phthisis bulbi following PBRT.
A 16-day-old boy with a family history of RB was referred to our institution. Initial examination revealed an extensive white mass in the right eye and a small tumor near the optic disk of the left eye. The patient was diagnosed with bilateral RB and treated with chemotherapy and focal ophthalmic therapy. The right eye showed shrinkage in the treatment course. The tumor control was not achieved bilaterally, and, therefore, PBRT was performed to preserve the eyes. However, the right eye became significantly phthisical following PBRT and ultimately required enucleation.
PBRT for RB may result in phthisis bulbi. Further investigations of its role and possible complications are warranted.
Pediatric Cataract Surgery Following Treatment for Retinoblastoma: A Case Series and Systematic Review
2022, American Journal of Ophthalmology
To determine the visual and refractive outcomes and the ocular and systemic complications of cataract surgery in eyes treated for retinoblastoma.
Retrospective consecutive case series and systematic review.
Children <18 years of age with retinoblastoma who underwent surgery for secondary cataract between 2000 and 2020 were reviewed. Medline (OVID), Embase, Web of Science, and the Cochrane database were searched from inception to August 2020.
A total of 15 eyes of 15 children were included. The mean age at retinoblastoma diagnosis was 12 months (median, 14; interquartile range [IQR], 4-19). Cataract developed at a mean age of 39 months (median, 31; IQR, 20-52), secondary to multiple treatments (n = 7), pars-plana vitrectomy (n = 3), external-beam radiotherapy (n = 2), laser (n = 2), and retinal detachment (n = 1). The mean preoperative quiescent interval was 44 months (median, 28; IQR, 15-64). Primary intraocular lens implantation was performed in 93%, posterior capsulotomy in 40%, and anterior vitrectomy in 33% of participants. Postoperatively, 100% had improved fundus visibility and 73% had improved vision. Complications included visual axis opacification (11 of 15), capsular phimosis (5 of 15), and zonulopathy (3 of 15). No patient developed intraocular recurrence, extraocular extension, or metastasis at a mean of 76 months (median, 78; IQR, 29-128) follow-up. The systematic review identified 852 studies, with 18 meeting inclusion criteria. Across all studies (n = 220 children), intraocular recurrence occurred in 6%, globe salvage in 91%, and extraocular extension and metastasis in <1%.
Modern retinoblastoma therapies, including intravitreal chemotherapy and vitrectomy, cause secondary cataract. Following cataract surgery, intraocular recurrence risk is low and extraocular spread is rare. Although surgery improves tumor visualization, visual prognosis may be limited by several factors. Challenges include biometry limitations and a high incidence of zonulopathy.
Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma
2020, Ophthalmology
Citation Excerpt :
Note that further information about uterine tumors (predominantly leiomyosarcoma) is provided below in a separate section. Recent reports have suggested that risk may be attenuated in the presence of specific genetic alterations,39 after treatment with proton radiotherapy,52,57 or both, but further research is required to confirm these findings. In some institutions, it is common practice periodically to image the head and neck region of retinoblastoma survivors.
To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma.
We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence.
Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center.
Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations.
Diagnosis and mortality from subsequent neoplasm.
Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent.
This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.
The role of proton therapy in pediatric malignancies: Recent advances and future directions
2020, Seminars in Oncology
Citation Excerpt :
Radiation has mostly been reserved for refractory or locally advanced disease, with early results by two studies demonstrating enucleation-free rates of 60% [138,139]. The larger of these included 60 eyes treated with received doses of 40–46.8 GyRBE, with no-in field recurrence and encouraging rates of vision preservation [138]. Preliminary data suggest that proton RT can lower the rate of RT-induced second malignancy [140], of crucial importance given many children harbor the Rb mutant gene which places them at higher risk for second tumors and radiation related tumors [141].
Proton radiotherapy has promised an advantage in safely treating pediatric malignancies with an increased capability to spare normal tissues, reducing the risk of both acute and late toxicity. The past decade has seen the proliferation of more than 30 proton facilities in the United States, with increased capacity to provide access to approximately 3,000 children per year who will require radiotherapy for their disease. We provide a review of the initial efforts to describe outcomes after proton therapy across the common pediatric disease sites. We discuss the main attempts to assess comparative efficacy between proton and photon radiotherapy concerning toxicity. We also discuss recent efforts of multi-institutional registries aimed at accelerating research to better define the optimal treatment paradigm for children requiring radiotherapy for cure.
Pediatric considerations for proton therapy
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Of all patients afflicted with cancer, children are the most likely to benefit from proton therapy. Because many such patients are cured, the development of late effects arising from treatment is a great concern. Protons have the advantage of reducing low-dose regions to surrounding normal tissues compared with photons. The available literature suggests that proton therapy has the same efficacy as photons with regard to local control, progression-free survival (PFS), and overall survival (OS) in many pediatric tumors. In the few reports available, proton therapy can reduce acute and late toxicity in many patients.
Lens Dose-Response Prediction Modeling and Cataract Incidence in Patients With Retinoblastoma After Lens-Sparing or Whole-Eye Radiation Therapy
2019, International Journal of Radiation Oncology Biology Physics
We retrospectively assessed the incidence of cataracts in patients with retinoblastoma (Rb) treated with either lens-sparing radiation therapy (LSRT) or whole-eye radiation therapy (WERT). A secondary aim of this study was to model the dose-response risk of cataract.
We reviewed 65 patients with Rb treated with radiation therapy (RT) at Children's Hospital, Los Angeles from 1997 to 2015. Eyes that were enucleated before RT or lacked follow-up eye examinations were excluded. All patients underwent computed tomography simulation, and mean lens dose data were collected. Follow-up ophthalmologic examinations and intraocular lens implant history were reviewed for cataracts. The primary event-free survival (EFS) outcome was cataract development. Eyes without cataracts were censored on the last date of eye examination or post-RT enucleation, if applicable. Kaplan-Meier estimates were used to compare EFS outcomes, and dose response was projected with Cox regression and logistic regression models.
Sixty-one patients (94 eyes) were analyzed with a median follow-up of 51.8 months. For eyes treated with WERT, cataracts developed in 71.7% versus 35.3% for LSRT. Median EFS for WERT and LSRT were 20.8 and 67.9 months, respectively. Compared with WERT, a significant EFS benefit was demonstrated for LSRT (P < .001). Mean lens dose had a significant effect on cataracts in both Cox regression and logistic regression models (P < .01). The mean lens dose of 7 Gy was projected to have a 5-year cataract incidence of 20% and 25% with the logistic and Cox regression models, respectively.
We report the first clinical data demonstrating significantly improved EFS in patients with Rb treated with LSRT. Through lens dose-response modeling, we validate a mean lens dose threshold of 7 Gy to keep cataract risk below 25%. Although RT is used less often for Rb owing to advances in chemotherapy delivery options, these findings are relevant for refining lens dose constraints, particularly in children who have received radiation dose near the orbit.

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: Conflict of interest: H.A.S. is a senior editor of the International Journal of Radiation Oncology, Biology, Physics.

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Clinical InvestigationProton Radiation Therapy for the Treatment of Retinoblastoma

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patient population

Patient and treatment characteristics

Discussion

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Eur J Cancer

Am J Ophthalmol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clinical Investigation
Proton Radiation Therapy for the Treatment of Retinoblastoma