Retinoblastoma with vitreous seeds is difficult to treat. As vitreous seeds have no blood supply, systemic chemotherapy typically fails to treat them.1 Therefore, vitreous seeds are considered the primary reason for treatment failure.1 In current retinoblastoma management, several treatment modalities for persistent or recurrent vitreous seeding from retinoblastoma are available; they include intra-arterial, intravitreal, or periocular chemotherapy; external beam radiotherapy (EBRT); and enucleation.2–9 Now, intravitreal chemotherapy is the major modality for treating vitreous seeds.1,10
EBRT is avoided if possible and considered the last treatment option before enucleation attributable to the risk of radiotherapy-related secondary cancers in children.11 However, there has been substantial advancement in EBRT techniques, and nowadays, proton beam radiation therapy (PBRT) is the favored treatment option for retinoblastoma.8,12 Because of its unique physical properties and the lack of an exit dose, PBRT has been shown to be the superior radiation therapy technique over other EBRT techniques as it provides a greater radiation dose to the target tumor with increased sparing of normal adjacent structures.8,11–13 This is associated with lower rates of radiation-induced normal tissue injury and malignancies when compared with other contemporary photon-based techniques.8,12,13
Studies reporting the outcomes of PBRT in patients with retinoblastoma are scarce.8,11,12,14,15 Here, we present the outcomes of PBRT specifically in patients with retinoblastoma with vitreous seeds.12
MATERIALS AND METHODS
Study Design and Participants
We retrospectively reviewed the medical records of retinoblastoma patients who were diagnosed at the Seoul National University Children’s Hospital and received PBRT at the Proton Therapy Center, National Cancer Center in Korea between June 2007 and August 2017. The patients were treated by PBRT initially at the time of diagnosis or subsequently with systemic chemotherapy and focal treatment.
We included children diagnosed with intraocular retinoblastoma with vitreous seeds who had either not been treated previously or had initially been treated with intravenous chemotherapy and focal treatment but showed no response to these strategies or showed a favorable response at first but developed tumor recurrence during or after the treatment. Patients treated by PBRT due to subretinal seeding and/or recurrent or a resistant solid mass were excluded.
We analyzed data on patient age and sex, family history, mutations in the RB1 gene, laterality, treatment status (naive vs. prior treatment), eye status (salvaged or enucleated), length of follow-up, and visual acuity of the treated eyes at the last visit. The Seoul National University Hospital Institutional Review Board reviewed and approved this study.
A plane computed tomography scan was taken with a 2-mm slice along the orbital space with or without an eye rotation using a suction cup.11,12 For tumors with vitreous seeding, the entire vitreous and retina were targeted with the anterior field edge placed just posterior to the lens and typically correlating with the ora serrata.8 Critical structures such as the ipsilateral lens, orbital bone and soft tissues, optic nerve, lacrimal gland, contralateral eye, temporal and frontal lobes, and pituitary gland were delineated as organs at risk.12
Proton beam planning was performed using a 3-dimensional treatment-planning system (Eclipse proton planning system version 8.1.2; Varian Medical System, Palo Alto, CA), and dose distributions were determined for each target volume and organs at risk.12 Three-dimensional proton plans were constructed with a single lateral or anterior oblique beam to provide a planning target volume of 95% of the prescribed dose.11 The prescribed doses were 3960 to 5040 cGy over 22 to 28 fractions. Radiation was given in daily 180-cGy fractions that were delivered 5 times per week. The proximal and distal margins for the targets were both 3 mm, and the border for smoothing and smearing margins were set to 0.5 and 1.2 mm, respectively. A smearing margin of 1.2 mm was used to allow for setup uncertainty. The block margins were set to 5 mm. To achieve maximum dose conformity, all beams were customized to the target, with brass apertures and Lucite compensators fabricated by a computer-driven milling machine, to specifications from the planning program.12,15
During the principal treatment setup, the patient was in the supine position under propofol-based total intravenous anesthesia. For each patient, a thermoplastic mask was fabricated. Daily eye setup and treatment field positioning were checked using the laser beams in relation to the suction cup centered on the cornea. The radiopaque wires built into the silicon suction cup served as an auxiliary marker for the patient’s bony anatomy.12
Patient Examinations, Systemic Chemotherapy, and Focal Treatment
Fundoscopic examinations were performed under general anesthesia, and fundus photos were taken using a RetCam (Clarity Medical System, Pleasanton, CA). The tumor stage was assigned at the initial evaluation, using the International Classification of Retinoblastoma (ICRB).5 Data on vitreous seeds included classification (class 1=dust, class 2=spheres, and class 3=clouds), extent of seeds (localized [≤1 quadrant] or diffuse [>1 quadrant]), and the location of tumor-producing seeds (defined by the tumor center located in the macula. macula-equator, or equator-ora).10,16
The combination regimen with carboplatin, etoposide, doxorubicin, cyclophosphamide, and vincristine was used for systemic chemotherapy before PBRT. In cases in which the treatment responses were poor to the combination treatment, the regimen was replaced by the second regimen composed of ifosfamide, etoposide, and carboplatin.17,18 Each cycle was repeated once per month for 1 week, for a total of 6 to 13 cycles, according to the patient’s condition and tumor status. Thermotherapy was performed, when the tumor volume was reduced, to allow focal treatment with the Oculight SLX diode laser (Iridex Corp., Mountain View, CA).
Outcomes of PBRT
Treatment success was defined as the regression of vitreous seeds, including decreased vitreous seed size and/or number. Treatment failure was defined as nonresponse of the vitreous seeds, increased vitreous seed size, and/or the development of new vitreous seeds. If the vitreous seeds showed no regression, enucleation was recommended after the funduscopic examination. Complications of radiation therapy (cataract, retinopathy, glaucoma, neovascularization, hemorrhage, and secondary malignancy) were also analyzed.
Characteristics of the Subjects
Among 181 patients with retinoblastoma, 10 (5.5%) were treated with PBRT. Among these, 6 were excluded from this study due to a resistant or recurrent solid mass (n=3), recurrent subretinal seeding (n=2), and a recurrent multiple mass with subretinal seeding (n=1); thus, the final study sample consisted of 4 subjects.
Four eyes per 4 patients received PBRT for retinoblastoma with vitreous seeds. The demographic and clinical characteristics of the included patients are summarized in Table 1. The mean age of the 4 patients at the onset of PBRT was 47.0±16.6 months (range, 24.5 to 64.4 mo). All patients had sporadic retinoblastoma; 3 had unilateral disease, and 1 had bilateral disease. RB1 gene evaluation was available for 3 patients; none of the patients showed an RB1 deletion, whereas 1 patient had an RB1 gene mutation.
On the basis of the ICRB criteria, all eyes treated by PBRT were classified as group D. Two patients had received prior intravenous chemotherapy and focal treatment; the remaining 2 patients received PBRT as the primary treatment approach. At the time of PBRT, all vitreous seeds were classified as clouds and were located in the macula-equator or equator-ora. Three patients showed diffuse seeds, whereas 1 patient had seeds localized to a single quadrant of the eye.
Outcomes of PBRT
Regression of the vitreous seeds and tumor control was achieved in 2 of 4 patients (50%; 1 patient with retinoblastoma with vitreous seeds in the naive eye and 1 patient with recurrent retinoblastoma that had previously been treated by intravenous chemotherapy [Fig. 1]). The remaining 2 patients (50%) underwent post-PBRT enucleation owing to progression (Fig. 2). The time between PBRT and enucleation in these 2 patients was 4 and 8 months, respectively. Post-PBRT ophthalmologic follow-up of the patients showed that their visual acuity measurements were 20/40 and 20/600, respectively. The time between PBRT and the last follow-up examination of the preserved eyes was 12 and 50 months, respectively. There were no immediate PBRT-related ocular side effects in the patients, and no patients died of retinoblastoma or developed metastatic disease. One patient developed a radiation cataract and successfully underwent cataract surgery 3 years after PBRT to prevent tumor spreading outside the eye as the eye demonstrated inactive disease.
In the present study, we evaluated the therapeutic effect of PBRT for retinoblastoma with vitreous seeds in naive and previously treated eyes. Although all patients had stage D retinoblastoma with vitreous seeds classified as clouds, the disease control and eye preservation rates were 50%, and functional vision was preserved in the successfully treated patients. No radiation-associated malignancies were observed in patients in the follow-up time period.
Eyes with extensive vitreous seeds are classified as groups D or E by the ICRB.19 Shields et al19 reported a success rate for systemic chemotherapy of only 30% for eyes with diffuse vitreous seeds. These results underscore the difficulty in vitreous seed control. Tumor cells can exist in vitreous or avascular subretinal spaces that chemotherapy cannot reach.1 Shields et al2 documented that intra-arterial chemotherapy could lead to complete control in 67% of vitreous seeds. Several large studies on intravitreal chemotherapy with safe techniques indicated excellent globe salvage rates of 83% to 100% with no cases of extraocular spread.4,9,20–22 However, intravitreal chemotherapy has not yet gained wide acceptance because of the apprehension of possible extraocular dissemination and pending standardization of dose and frequency of administration.7 Moreover, intravitreal melphalan chemotherapy also has associated toxicity.1 Studies have demonstrated a dose-dependent toxic effect on retinal pigment epithelial cells and vision-threatening complications such as vitreous hemorrhage or serous retinal detachment.1,20,22–25
The success rates for salvage radiotherapy for recurrent vitreous seeding range between 50% and 70%; salvage radiotherapy has expected short-term and long-term side effects such as cataracts, retinopathy, glaucoma, bony hypoplasia of the orbit, and secondary malignancies.26–28 A report from the Boston group indicated a globe salvage rate of 77% for groups C and D eyes, and overall globe salvage rates for PBRT appear to be similar to those for intensity-modulated radiotherapy.8,15 Our study showed a 50% success rate for treating cloud-pattern vitreous seeding, and useful vision was preserved in the successfully treated eyes. The success rate of our study is not promising. However, our outcome might have been affected by seed classification. Berry et al1 recently reported that not all vitreous seeds are created equal and that seed classification was predictive of treatment outcomes in patients with retinoblastoma. Vitreous seeds classified as clouds were more likely to occur in the equator-ora region of the fundus in a diffuse pattern.16 Eyes with this seeding pattern showed lack of intravitreal therapeutic response and required significantly more intravitreal injections than eyes with dust or sphere seeding patterns.1,29,30
PBRT-related complications include cataracts, retinopathy, glaucoma, neovascularization, hemorrhage, bony hypoplasia of the orbit, and secondary malignancies.8,11,31 Mouw et al8 reported that cataracts were the most common complication of PBRT. In our study, 3 patients had no PBRT-related ocular side effects; only 1 patient developed a radiation cataract and successfully underwent cataract surgery 3 years after PBRT. No secondary malignancies were noted in this study, although the follow-up time was clearly not long enough to see any secondary tumors. Because of the entrance of the proton beam through the lateral or anterior oblique treatment portal, cosmetic side effects, including orbital hypoplasia, hyperpigmentation, and soft tissue fibrosis can occur.8 We did not evaluate PBRT-related cosmetic issues in this study, as it was a retrospective review, but no procedures to address cosmetic issues were recorded. The actual rates of cosmetic side effects of PBRT might be higher than the reported rates due to a lack of standardized reporting.8,14
This study is limited by its retrospective nature and the small number of subjects. Moreover, the mean follow-up period was short; a longer follow-up period is needed to confirm the long-term safety and efficacy of PBRT. Although tumors with RB1 gene mutations appear to be more sensitive to radiation, we could not analyze this due to the small number of cases.11
In conclusion, we show that PBRT for untreated, recurrent, or recalcitrant vitreous retinoblastoma seeds resulted in seed control. The successfully treated eyes did not require subsequent enucleation. PBRT might be a viable treatment option for vitreous seeds in patients with retinoblastoma as it allows patients to retain useful vision in the treated eyes.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
vitreous seeds; retinoblastoma; proton beam radiotherapy