INTRODUCTION
Plaque brachytherapy is a form of local radiation delivered to the eye via a radioactive device that is stitched onto the eye directly over the tumor inside the eye. It provides focused and localized dose delivery without damaging surrounding normal structures. Plaque brachytherapy is an effective eye- and vision-sparing alternative to enucleation for patients with intraocular tumors. It was introduced in 1930 by Moore et al.[,] to treat intraocular tumors, mainly retinoblastoma and choroidal melanoma. Various radioisotopes such as I-125, Pd-103, Sr-90, and Cs-131 have been utilized for plaque brachytherapy.[,] However, the most commonly used ophthalmic plaques are based on I-125 and Ru-106. Treatment with Ruthenium-106 plaque is preferred as it is a beta emitter, and hence, the radiation gradient surrounding ruthenium plaque is steeper than that found with the gamma emitter. Therefore, Ruthenium-106 plaque provides reduced dose delivery to normal ocular structure and maximum radiation to the tumor base. However, till recently, this plaque needed to be imported in India, and hence, the availability was limited due to its exorbitant price. The Bhabha Atomic Research Center (BARC) introduced indigenous ruthenium plaque to make plaque brachytherapy treatment available and affordable to all needy patients in India. However, to the best of our knowledge, peer-reviewed publications reporting clinical feasibility and efficacy of the indigenous Ru-106 plaque for the treatment of retinoblastoma and other ocular tumors are not available till date. Herein, for the first time through this case series, we describe our experience with the indigenous Ru-106 plaque as a secondary treatment modality in a spectrum of ocular tumors.
Plaque: We used the BARC make notched eye plaque with the outer diameter 21 mm, active core diameter 18.5 mm, and spherical radius of 12 mm. The plaque comprised three silver disks joined together: the back cover sliver disk of 0.9 mm thickness, the core disk of 0.2 mm thickness coated with Ru-106, and the inner window pane of 0.1 mm thickness. The initial nominal activity of the plaques was close to 45 MBq. The useful life of the plaque is about 2 years, during which time it can be used a maximum of 50 times.
BARC provided the calibrated plaques with measured dose rates at 1 and 2 mm depths in water from the plaque’s inner concave surface. Also, it provided dose rate in a tabular form along the plaque axis for up to a depth of about 10 mm. For the plaque supplied to us, the activity was 40.4 MBq and the dose rate was about 180 mGy/min at the depth of 2 mm on the day the first case was treated.
Ru-106 is a pure β− emitter radionuclide which is in secular equilibrium with Rh-106. Ru-106 decays with a half-life of 371.5 days to Rh-106 emitting 0.039 MeV β− radiation, and its daughter product Rh-106 decays with a half-life of 29.8 s to Pd-106 emitting 3.54 MeV β− radiation. The main contributor to therapeutic dose is the beta spectrum of Rh-106.
Radiobiology
The beta radiation from the plaque has a linear energy transfer (LET) value similar to other forms of radiation commonly used in radiotherapy, such as gamma-rays, x-rays, and electrons. Therefore, radiobiological effectiveness (RBE) of the beta-rays emitted from the plaques is not different from the other forms of radiation. However, unlike in external beam radiotherapy (EBRT) where dose is delivered in discrete fractions at a high dose rate, each fraction lasting a few minutes, the dose from the plaque is delivered in a continuous mode over a few hours at a relatively low dose rate. As a result, the biologically effective dose (BED) varies between EBRT and plaque therapy. The difference depends upon dose rate, repair rate constant of sublethal damage, and the α/β values of the different tumors and normal tissues. The β− radiation emitted from the Ru-106 plaque has a range of 17 mm in water/tissue, and hence, sparing of the normal tissues beyond the tumor is superior to that seen with gamma-emitting plaques.
CASE DESCRIPTION
Case 1
A 3-year-old child was brought by his parents to this center in 2018 with complaints of white reflex in the left eye since 3 months. Initial examination under anesthesia revealed group A retinoblastoma in the right eye and group E retinoblastoma in the left eye [Figure 1a and b]. Magnetic resonance imaging (MRI) orbit showed lobulated mass in the left eye, occupying the whole vitreous [Figure 1c, d]. However, there was no involvement of the retroocular optic nerve and sclera. Systemic chemotherapy was started as the patient had bilateral retinoblastoma. Six cycles of chemotherapy were given to the patient. He also underwent enucleation with implant in the left eye under general anesthesia [Figure 1f]. Patient was given customized ocular prosthesis in the left eye after 1 month. In the right eye, focal consolidation was done with cryotherapy at an interval of 4 weeks [Figure 1e]. Another six cycles of chemotherapy were also given as retrolaminar part of the optic nerve was found to be involved. Patient was regularly followed up for 6 months. However, recurrence of tumor was detected in the inferotemporal quadrant over the edge of chorioretinal scar of cryotherapy during the follow-up period [Figure 2a]. MRI orbit was repeated, which showed lobulated mass in the posterior part of eye [Figure 2b]. Patient was taken up for plaque brachytherapy as the basal diameter of the recurrent tumor was more than 6 mm and thickness was more than 4 mm. The BARC Ru-106 plaque was used for the first time at our center for treating the recurrent tumor in the current case [Figure 2c and d].
Open multimedia modal
Figure 1
Open multimedia modal
(a) Fundus photograph showing whitish yellow endophytic lesion in the inferotemporal quadrant of the right eye. (b) Fundus photograph showing yellowish white lesion occupying the whole vitreous in the left eye. (c) MRI orbit showing enhancing lesion in inferotemporal quadrant in right eye and lobulated heterogeneously enhancing lesion occupying two third of vitreous arising from the posterior aspect of eyeball in left eye. (d) MRI orbit showing no involvement of optic nerve and sclera. (e) Fundus photograph showing regressed tumor in the right eye. (f) Clinical photograph showing enucleated left eye. MRI = magnetic resonance imaging
Open multimedia modal
Figure 2
Open multimedia modal
(a) Fundus photograph showing recurrence of tumor in the inferotemporal quadrant over the edge of chorioretinal scar of cryotherapy with feeder vessel at the periphery with intrinsic vascularity. (b) MRI orbit showing well defined, lobulated, intraocular heterogenous enhancing lesion in the inferotemporal quadrant, measuring 8.1 mm × 7.7 mm × 4.8 mm in size, with no involvement of optic nerve in the right eye (red arrow) and post enucleation status on the left side (black arrow). (c) Clinical photograph showing indigenous ruthenium plaque. (d) Intraoperative image showing the ruthenium plaque over the tumor. (e) Fundus photograph showing the regressed tumor after 1 month. (f) Fundus photograph showing completely regressed tumor with no sign of recurrence after 6 months. MRI = magnetic resonance imaging
Treatment planning and implant duration
The tumor location and size were assessed on the MRI for planning purposes. The dose was prescribed at the tumor apex. Prescription dose was decided based on the available literature. Duration of irradiation/plaque implantation was calculated with the dose rate value at the tumor apex depth using the BARC-supplied dose rate table and the prescribed dose. We soon intend to use the BARC-provided plaque simulator software for assessing 2D and 3D dose distributions.
Surgical procedure
The procedure was done under general anesthesia. The tumor was located over the outer surface of sclera in the inferotemporal quadrant by indirect ophthalmoscopy with scleral indentation technique. Initially, a dummy plaque was inserted over the tumor for applying preplaced partial scleral thickness suture. The dummy plaque was replaced with hot plaque, which was anchored to the sclera with 5-0 Ethibond nonabsorbable suture through the plaque eyelets to ensure maximum adherence between the plaque and sclera [Figure 3]. The plaque was implanted for 9.47 h to deliver 40 Gy dose to the tumor apex.
The patient was advised lubricants for 1 month. The patient was seen again after 1 month, and fundus examination showed complete regression of the tumor [Figure 2e]. His condition has remained stable even after 6 months of follow-up, with no sign of recurrence and no evidence of radiation-induced complication [Figure 2f].
Case 2
A 35-year-old patient presented with gradual loss of vision in the right eye since 1 year. His distant visual acuity in the right eye was 20/400 and in the left eye was 20/20. Fundus examination in the right eye showed well-defined orangish lesion along the superotemporal quadrant near to the optic disk, about 4 × 4 mm in size, with subretinal fluid extending up to macula [Figure 4a, b]. He was diagnosed with choroidal hemangioma right eye. Photodynamic therapy with verteporfin was done; however, leakage was found to be persisting. Plaque brachytherapy using indigenous ruthenium plaque was performed as the basal diameter of the tumor was more than 4mm in size and thickness more than 4 mm in size. A radiation dose of 30 Gy was given to the tumor apex. The duration of the plaque implantation was 7.88 h. The patient was evaluated after 1 month, and fundus examination showed regression of the tumor with decrease in subretinal fluid [Figure 4c, d].
Open multimedia modal
Figure 4
Open multimedia modal
(a) Fundus photograph showing a well-defined orange-red mass near to the disk on the temporal aspect and within the arcade. (b) Optical coherence tomography showing subretinal fluid at the fovea. (c) Fundus photograph showing regressed tumor at 1 month posttreatment. (d) Optical coherence tomography showing decreased subretinal fluid at the foveal region following ruthenium plaque radiotherapy. (e) Fundus photograph showing an elevated lesion in the superonasal quadrant near to the optic disk. (f) Optical coherence tomography showing subretinal fluid at the macula. (g) Fundus photograph showing regressed tumor at 1 month posttreatment. (h) Optical coherence tomography showing decreased subretinal fluid at the foveal region following treatment
Case 3
A 37-year-old patient reported with complaints of diminished vision in the right eye since 6 months. His best corrected visual acuity in the right eye was 20/200 and in the left eye was 20/20. Fundus examination showed an elevated lesion, about 8 × 6 mm in size, in the superonasal quadrant near to the optic disk with presence of subretinal fluid at the macula [Figure 4e, f]. He was diagnosed as a case of choroidal hemangioma. Patient was initially managed with photodynamic therapy and transpupillary therapy, but he did not respond. As the tumor was active, he was taken up for plaque brachytherapy with a dose of 30 Gy at the tumor apex. The plaque was implanted for a duration of 9.94 h. The patient was seen after 1 month, and posterior segment evaluation showed regressed tumor with decrease in subretinal fluid [Figure 4g and h].
Case 4
An 89-year-old patient reported with complaint of growth in his left eye (LE) since 1 year, which was gradually increasing in size. Slit-lamp examination showed an elevated papillomatous lesion, about 8 × 6 × 2 mm in size, located on the temporal side, extending from 3 o’ clock to 6 o’ clock position, extending 2 mm into the cornea, with feeder vessel at the base of the lesion [Figure 5a]. Anterior segment optical coherence tomography showed thickened hyperreflective epithelial layer and an abrupt transition from normal to abnormal epithelium [Figure 5b]. He was diagnosed as a case of ocular surface squamous neoplasia (OSSN) based on clinical features. Wide surgical excision with 3-mm uninvolved conjunctival margin using no touch technique was performed. The defect was covered with amniotic membrane graft and secured with fibrin glue [Figure 5c]. Histopathologic examination showed involvement of scleral bed by the tumor; hence, the patient was advised plaque brachytherapy [Figure 5d]. The Ru-106 plaque was placed over the scleral bed and was removed after 5.5 h after giving a radiation dose of 50 Gy [Figure 5e]. Patient was followed up for 6 months and showed no sign of recurrence [Figure 5f].
Open multimedia modal
Figure 5
Open multimedia modal
(a) Slit-lamp photograph showing leukoplakic OSSN over the temporal aspect of the left eye. (b) Anterior Segment Optical Coherence Tomography (AS-OCT) image of OSSN showing thickened hyperreflective epithelial tissue (black arrow). (c) Clinical photograph showing amniotic membrane graft in place post wide local excision with no sign of recurrence after 1 month. (d) Histopathology image showing hyperplastic squamous epithelium with full-thickness dysplasia and invasion into the subepithelium. (e) Clinical photograph showing indigenous ruthenium plaque over the sclera bed. (f) Slit-lamp photograph showing no sign of recurrence after 6 months. OSSN = ocular surface squamous neoplasia
DISCUSSION
Multiple treatment modalities have been available for treatment of ocular tumors, which include chemotherapy, transpupillary thermotherapy, cryotherapy, radiotherapy (EBRT and plaque brachytherapy), and surgery depending upon the size, location, and extension of the tumor.[,] Plaque brachytherapy is recommended when the basal diameter of intraocular tumor is between 4 and 16 mm and its thickness is between 4 and 8 mm.[] In OSSN, plaque brachytherapy is indicated when there is evidence of corneal stromal or scleral invasion.[] Ru-106 plaque is the preferred brachytherapy mode as it provides focused radiation at the tumor apex without damaging adjacent structures. In addition to this, Ru-106 is cost effective as it has a longer half-life (373.6 days).[] One plaque can be used for a maximum of 50 times (patients), and its shelf life is more than a year. BARC, Mumbai, in India developed the first indigenous Ru-106 plaque as part of the Make in India initiative. The current case series has demonstrated that the indigenous Ru-106 plaque is an effective treatment modality. It has also shown that it is simple to use and can be placed easily over the site of the tumor. The tumors completely regressed within 1 month after treatment, with no sign of recurrence at 6 months follow-up in all four cases. We did not encounter complications associated with the localized radiation, like dry eye, cataract, radiation papillopathy, and retinopathy. For the first time, Khetan et al.[] performed plaque brachytherapy of intraocular tumors in their study population using BARC I-125 Ocu-Prosta seeds and achieved good control of intraocular tumor with decreased complications. To our knowledge, the case series presented in this paper is the first series from the Indian subcontinent which has demonstrated the effectiveness of indigenous Ru-106 plaque in ocular tumors. This case series also highlights the need for locally made products to make the treatment available and accessible to everyone at all oncology centers. The limitation of this case series is its small sample size and short follow-up. Radiation-related complications have been reported 5 years after the procedure in some published studies. Hence, longer follow-up and study of a larger population need to be carried out to validate the safety and efficacy of indigenous ruthenium plaque.
CONCLUSION
The indigenous Ru-106 plaque-based brachytherapy is an effective treatment modality in a spectrum of ocular tumors and is a safe alternative to enucleation and EBRT. It achieved excellent tumor control with minimal side effects in the current case series. The indigenous Ru-106 plaque has also made brachytherapy treatment affordable, particularly in developing countries, and is simple to handle.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Army Hospital Research and Referral) and with the 1964 Helsinki Declaration and its amendments or comparable ethical standards. This manuscript did not involve any kind of animal research. All the authors consent to the publication of this manuscript in Journal of Cancer Research and Therapeutics.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Keywords:
Brachytherapy; indigenous; ruthenium