Therapeutic Options for Retinoblastoma

Pia R. Mendoza, MD; Hans E. Grossniklaus, MD

Disclosures

Cancer Control. 2016;23(2):99-109. 

In This Article

Management

Chemotherapy

Intravenous. Systemic chemotherapy generally involves a combination 2-, 3-, or 4-drug regimen delivered through an intravenous catheter. Three classes of agents are commonly employed: DNA-crosslinking agents (carboplatin, cisplatin), DNA topoisomerase 2 inhibitors (etoposide, topotecan, teniposide) and Vinca alkaloids (vincristine; Fig 1). The most commonly used regimen is vincristine/etoposide/carboplatin.[11]

Figure 1.

Chemotherapeutic agents used in retinoblastoma. Alkylating agents such as melphalan cause DNA intra–strand-linking and cross-linking, resulting in DNA damage and disruption of transcription. Topoisomerase inhibitors such as etoposide and topotecan cap free double-strand breaks in DNA, preventing DNA repair and apoptosis. Platinum-based agents such as carboplatin bind DNA bases, resulting in kinked DNA. Vinca alkaloids such as vincristine bind tubulin dimers and block mitotic spindle formation.
Reprinted from Grossniklaus HE. Retinoblastoma. Fifty years of progress. The LXXI Edward Jackson Memorial Lecture. Am J Ophthalmol. 2014;158(5):875–891, with permission from Elsevier.

Chemoreduction via systemic chemotherapy was introduced as a management option for retinoblastoma in the mid-1990s following preliminary observations that systemic chemotherapy delivered prior to external beam radiotherapy contributed to tumor control and ocular salvage.[19] A subsequent study on eyes treated with chemoreduction combined with focal treatments (cryotherapy, thermotherapy, or plaque radiotherapy) demonstrated tumor regression and decreased need for additional external beam radiotherapy and enucleation.[20] This was a major advancement in management because it was evident that satisfactory tumor control could be attained with systemic chemotherapy while saving the eye and avoiding the adverse events of external beam radiotherapy.[20] Using the International Classification of Retinoblastoma, treatment success was found in 100% of group A eyes, 93% of group B eyes, 90% of group C eyes, and 48% group D eyes.[14] This launched the so-called "systemic chemotherapy era" (1990s to 2006); however, with the advent of local routes of administration (intra-arterial and intravitreal), use of systemic chemotherapy has decreased in recent years.[14]

Intravenous chemotherapy is indicated as initial therapy for bilateral advanced disease in which attempts are made to salvage both eyes. Many centers use systemic chemotherapy in bilateral (germline) retinoblastoma for intraocular retinoblastoma control as well as to prevent metastasis, reduce the likelihood of the development of pineoblastoma, and to reduce the long-term risk of secondary cancers.[17,18] Systemic chemotherapy is also utilized as adjuvant treatment to prevent metastasis following enucleation in patients with optic nerve invasion posterior to the lamina cribrosa, massive choroidal invasion, or any combination of optic nerve and choroidal invasion.[21] The treatment regimens used include vincristine/etoposide/carboplatin, vincristine/doxorubicin/idarubicin/cyclophosphamide, or hybrid regimens, typically delivered monthly for 6 to 9 months.[22] A major obstacle to use of intravenous chemotherapy in retinoblastoma is the blood–retina barrier, which limits the entry of some chemotherapeutic agents into the eye, thereby reducing their efficacy.[23] Systemic chemotherapy for retinoblastoma is generally safe and effective, but it is not without adverse events, such as neurotoxicity, hyponatremia, nephrotoxicity, ototoxicity, and secondary leukemia. Treatment failure in the form of persistent vitreous seeds, subretinal seeds, and intraretinal tumors following therapy have been attributed to the inability of the treatment drugs to reach the tumor.[24] Tumor resistance or unresponsiveness to chemotherapy is thought to occur more often in well-differentiated tumors, presumably because cells are not cycling, so they are less likely to respond to treatment modalities affecting cell division.[25]

Intra-arterial. In the late 1980s, melphalan was found to be effective for the management of retinoblastoma in vitro.[26] Yamane et al[27] and Suzuki et al[28] then began to treat patients with intracarotid artery melphalan, developing a technique to safely and effectively cannulate the ophthalmic artery for chemotherapy infusion. In the United States, intra-arterial chemotherapy (IAC) was initially used by Abramson et al.[29] IAC involves transfemoral catheterization with advancement into the ophthalmic artery, which is where melphalan, topotecan, or carboplatin is infused. The medication is slowly delivered for 30 minutes in a pulsatile fashion with care to not occlude the artery and to minimize reflux into the internal carotid artery. Most patients receive 3 monthly sessions. Melphalan is the most frequently used agent, with topotecan added if extensive vitreous seeding is present.

Generally, IAC is employed for unilateral or nongermline retinoblastoma, recurrent tumors following previous intravenous chemotherapy or plaque radiotherapy, recurrent subretinal seeds involving at least 2 quadrants, recurrent vitreous seeds, or, if the patient wishes to avoid systemic therapy, enucleation can be considered if consent is obtained. In a 5-year experience with IAC, complete regression was achieved for solid tumors in 94%, for subretinal seeds in 95%, and for vitreous seeds in 87% of study patients.[30] In recent years, globe-salvage results (85%–94% globe salvage rate in group D tumors with primary IAC) have been reported in study patients with advanced retinoblastoma.[30,31] In some centers, most group D eyes are primarily treated with IAC, and, on occasion, group D and E eyes are managed with combined intravenous chemotherapy followed by intra-arterial chemotherapy — particularly if the patient has advanced bilateral disease or disease in a single eye.[7] Fair success has been reported in group E tumors with total retinal detachment cautiously managed with initial IAC.[32,33] Treatment of more advanced disease with initial IAC has also not been shown to compromise survival rates.[7] After adequate reduction is visualized and subretinal fluid is resolved, complete consolidation with either thermotherapy or cryotherapy and supplemental intravitreal chemotherapy after IAC are commonly performed. Consolidation is generally performed during the second or third cycle of chemoreduction.

In infants younger than 3 months who weigh less than 7 kg, IAC is initially deferred to allow the femoral artery to grow before attempting catheterization. In such cases, patients are treated with 1 to 2 doses of single-agent carboplatin as bridge therapy before definitive IAC.[34]

Reports of high rates of efficacy of IAC abound, but studies also exist on its associated ocular toxicities.[35–37] Use of intra-arterial infusion of melphalan and carboplatin compromise the ocular vasculature in nonhuman primates and induces inflammation and leukostasis in human retinal endothelial cells.[35,36] Other complications include vitreous hemorrhage, microemboli to the retina and choroid, myositis, eyelid edema, orbital congestion with resulting dysmotility, choroidal atrophy, optic atrophy, ophthalmic artery stenosis, and branch-retinal artery occlusion resulting in blindnesss.[37]

A major drawback to this therapy is that only skilled neurosurgeons and/or interventional radiologists at major cancer centers can treat patients using IAC.[38] The therapy is also expensive.[39] In developing countries, IAC is not available or is too costly, so enucleation as initial therapy is still a mainstay of treatment for advanced retinoblastoma.[40] In addition, a study has shown that initial chemotherapy prior to enucleation for advanced retinoblastoma can mask pathological evidence of tumor extension, thus leading to reduced surveillance and the undertreatment of high-risk disease — thereby increasing the risk of metastatic death.[41]

Intravitreal. The major question encountered in the management of retinoblastoma is how to treat subretinal and vitreous seeds of tumor unresponsive to laser treatment, conventional chemoreduction therapy, or IAC.[24] Treatment of vitreous seeds is challenging due to lack of vasculature in the vitreous. Another route of administration developed to address this problem is the intravitreal method, which involves injecting the therapeutic agent into the vitreous cavity of the eye through the pars plana under aseptic precautions.

Although health care professionals were initially skeptical of injecting drugs through the sclera into the vitreous for fear of tumor spread along needle tracks, techniques for safe and effective intravitreal injections have been developed. Intraocular pressure is first lowered prior to the injection. A small-volume dose of melphalan, topotecan, or a combination of both is injected into the eye using a fine needle (30- or 32-gauge) and the needle is frozen with a cryoprobe as it is withdrawn from the eye to prevent tumor seeding.[42] The first-line indication for intravitreal chemotherapy includes vitreous seeds refractory to standard therapy and recurrent vitreous seeds after previous therapy.[43,44]

In an analysis of 57 eyes with viable recurrent vitreous seeds, intravitreal melphalan led to eye salvage in 51% of eyes after 10 years of follow-up; no cases of extraocular extension were reported during that time.[45] A systematic review showed that proper technique does not increase the risk of tumor spread.[46] Treatment of retinoblastoma with recurrent vitreous seeds has been reported to have a success rate of 83%.[47] The number of injections depends on the response, and 6 injections delivered weekly or biweekly is recommended. Reported adverse events include transient vitreous hemorrhage, chorioretinal atrophy, and extraocular tumor spread.[42,48,49]

Melphalan is the most commonly used drug for intravitreal injections. Although it caused no systemic toxicity in humans or rabbits, melphalan did result in significant retinal toxicity at high doses and lower but safer doses only achieved incomplete tumor control.[42,50]

Periocular. Chemotherapeutic agents may be periocularly injected, either as subconjunctival or subtenon. Periocular injection enables transcleral drug delivery, using the large surface area of the sclera and its high permeability to small molecules without the danger of puncturing the globe.[51] Periocular chemotherapy achieves levels within the vitreous rapidly and at levels 6 to 10 times higher than the intravenous route.[52] In general, periocular injection of chemotherapeutic agents has been used for retinoblastoma control as an adjunct to systemic chemotherapy and, on occasion, to treat tumor recurrence. Either carboplatin or topotecan can be employed. The first-line indications for periocular chemotherapy are bilateral advanced group D or E eyes in which a higher local dose of chemotherapy is needed, treatment of vitreous seeds, and recurrent localized tumor. Subtenon chemotherapy using carboplatin can increase tumor control, especially if it is coupled with intravenous chemoreduction. Subtenon carboplatin showed initial favorable results as single therapy, but long-term follow-up revealed a high failure rate as initial treatment; therefore, it should be combined with other therapeutic approaches.[53]

Complications of periocular chemotherapy include orbital and eyelid edema, ecchymosis, orbital fat atrophy, muscle fibrosis leading to strabismus, and optic atrophy.[53–55] Because of its significant toxic effects, periocular chemotherapy is rarely used in current practice.

Focal Therapy

Thermotherapy/Transpupillary Thermotherapy. This type of focal therapy uses an 810-nm diode laser directly on the tumor to heat it up to subcoagulation temperatures of 42 to 60 °C to induce a cytotoxic effect. It is used for local control and for small (< 4.5-mm base and 2.5-mm thickness) tumors posteriorly located to the equator of the globe. In cases of macular or juxtapapillary tumors, consolidation should be performed with caution so as to protect the optic disc and neurosensory papillomacular bundle. The tumor may be observed while on chemoreduction and, if unresponsive, foveal-sparing thermotherapy may be administered. In an analysis of 68 macular retinoblastomas treated with chemoreduction, tumor recurrence occurred in 17% of those consolidated with foveal-sparing thermotherapy compared with 35% of those observed without consolidation.[56] Complications of transpupillary thermotherapy include iris atrophy, focal cataracts, tumor seeding into the vitreous, and retinal fibrosis, transition, and vascular occlusion.

Laser Photocoagulation. This type of therapy uses an 520-nm argon laser to coagulate the blood supply of the tumor by generating heat with temperatures in excess of 65 °C within the treatment spot. Direct photocoagulation to the tumor must be avoided. A second mechanism occurring around the ring of tissue beyond the laser spot is the increase in temperature to a thermotherapeutic range (45–60 °C). In this region, synergism exists with carboplatin, so this laser treatment is typically performed within 24 hours of the intravenous chemotherapy cycle. Small posterior tumors without seeding respond well to laser photocoagulation. It is not used for tumors impinging on the fovea, because of the risk of compromising a patient's central vision. In such cases, some form of chemotherapy can be used to shrink the tumor prior to the start of definitive laser treatment. Photocoagulation is also used to treat tumor-associated retinal neovascularization. Complications include vitreous seeding if the laser power is too high, and retinal fibrosis, traction, and vascular occlusion.

Cryotherapy. Cryotherapy involves a cryoprobe by which liquid nitrogen is delivered and directly applied to the outer surface of the sclera adjacent to the tumor. It is suitable for small (< 3.5-mm base and < 2-mm thickness) tumors anteriorly located to the equator of the globe. Complications of cryotherapy include retinal tears and detachment, proliferative vitreoretinopathy, and chorioretinal atrophy.

Plaque Brachytherapy. This type of treatment refers to implantation of radioactive material on the sclera over the base of the tumor. Tissue absorption of ionizing radiation causes DNA damage and cell death. Because retinoblastoma has a high rate of proliferating cells, it is quite radiosensitive. Brachytherapy is used for solitary, medium-sized tumors (6–15 mm and > 3 mm from the optic disc or fovea) and, if little subretinal fluid is present, plaque radiotherapy can generally be used to achieve tumor control. Iodine-125 and ruthenium-106 isotopes are the most common source of radiation currently used in brachytherapy for retinoblastoma to deliver 40 to 45 Gy to the apex of the tumor. In addition to treatment for retinoblastoma, ocular brachytherapy is commonly used for uveal melanoma, in which a clinician uses a similar surgical technique of plaque application of suturing to the episcleral surface but uses a lower dose of radiation. Complications of plaque brachytherapy include radiation retinopathy and optic neuropathy.[18]

Consolidation alone may be used in group A and B tumors. Bilateral cases with small, extrafoveal tumors can be managed with focal treatments alone. In asymmetric disease, a single eye can be managed with focal techniques and the other with enucleation or intra-arterial chemotherapy with or without systemic chemotherapy.[7] The desired end point is tumor regression in the form of a completely calcified tumor (type 1 regression) or a flat chorioretinal scar (type 4 regression).

Enucleation

Enucleation remains a favored approach in cases of extensive retinoblastoma with buphthalmos, neovascular glaucoma, aqueous seeding, and transcleral extension (advanced group E eyes) — particularly for unilateral cases with no likelihood of functional vision.[6] Surgery involves careful removal of the eye with minimal globe trauma to prevent tumor seeding into the orbit, and then excising a long section of optic nerve for proper histopathological evaluation.[57] Following enucleation, an orbital implant is placed to provide the socket with enough volume and allow the 4 rectus muscles to attach for motility. Immediately after enucleation, fresh tissue should be harvested on a separate tray for genetic studies.

A corollary to enucleation is the adequate histopathological evaluation of globe pathology, because retinoblastoma with histological features signifying a high risk of metastasis requires adjuvant intravenous chemotherapy.[58] High-risk features include choroidal invasion, retrolaminar optic nerve invasion, scleral and orbital invasion, and anterior chamber invasion. An analysis of 1,020 study patients with high-risk features after enucleation showed that 24% of study volunteers at high risk developed metastasis if not treated with adjuvant chemotherapy, whereas 4% of these study patients had metastasis if treated with chemotherapy.[59]

The regimen for adjuvant chemotherapy is vincristine/etoposide/carboplatin for 4 to 6 cycles.

External Beam Radiotherapy

External beam radiotherapy can be used to treat eyes unresponsive to other treatments, those with a tumor located at the optic nerve resection margin (36 Gy to orbit and 10 Gy boost to chiasm), and as treatment of extraocular retinoblastoma such as those extending through the sclera, orbit, or intracranially (40–45 Gy).[18]

External beam radiotherapy is rarely used and employed only when necessary because of its subsequent risks. It is known to cause midfacial hypoplasia in young patients and increase the risk of development of soft-tissue sarcomas, brain tumors, osteosarcomas, and other cancers.[60] In patients with bilateral disease, the incidence of secondary malignancy at 50 years from diagnosis of retinoblastoma is 21% in patients who were not treated vs 38% for those who were treated with radiation.[61–63] If possible, any radiation (including radiography, computed tomography, and external beam) should be avoided in individuals with heritable retinoblastoma to minimize their lifetime risk of developing secondary cancers.

Extraocular Therapy

Although their incidence is rare in developed countries, cases of extraocular disease are occasionally seen in neglected or inadequately treated patients.[64,65] Tumors may directly extend through emissary vessels of the sclera into the orbital soft tissue surrounding the eye. Treatment of orbital retinoblastoma includes systemic chemotherapy and external beam radiotherapy (40–45 Gy) with a rate of cure between 60% and 85%.[18] Treatment may also extend to the optic nerve into the brain and meninges with subsequent seeding of spinal fluid. Most recurrences occur in the central nervous system and are associated with a low cure rate; regimens proven to be effective include vincristine, cyclophosphamide, doxorubicin, and platinum as well as epipodophyllotoxin-based drugs.[66] No preclinical or clinical evidence supports the use of intrathecal chemotherapy. Craniospinal irradiation using 25 to 35 Gy is sometimes provided. Retinoblastoma may also hematogenously spread to the bone marrow, bones, lungs, or liver. For metastatic disease, multiple-agent, high-dose chemotherapy and autologous hematopoietic stem cell transplantation can be administered as rescue therapy.[67] The Children's Oncology Group developed a prospective, multi-institutional, international trial for metastatic retinoblastoma, and data will be available in early 2016; that study hopes to define differences in site of metastasis and outcome.[68]

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