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Intravitreal Chemotherapy for Retinoblastoma
Advances in Ophthalmology and Optometry 1 (2016) 273–285
ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY
Intravitreal Chemotherapy for Retinoblastoma Roomasa Channa, MD, Jithin Yohannan, MD, Mary Aronow, MD* Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA
Keywords
Retinoblastoma Intravitreal chemotherapy Melphalan Vitreous seeds
Key points
Intravitreal chemotherapy is a promising therapy when used in conjunction with systemic and/or intra-arterial chemotherapy for the treatment of retinoblastoma associated with vitreous seeding.
Intravitreal chemotherapy has been shown effective and safe when used in the appropriate setting.
There are several unique safety considerations regarding the administration of chemotherapy by intravitreal injection for the treatment of retinoblastoma.
INTRODUCTION Retinoblastoma is the most common pediatric intraocular malignancy. The age-adjusted incidence is 11.8 cases per million children, which in the United States translates to approximately 300 new cases annually [1]. Retinoblastoma results from either somatic or germline mutations within RB1, a tumor suppressor gene, located on the long arm of chromosome 13 at region 14. Children most frequently present with leukokoria (or a white pupil reflex) [2]. Involvement may be unilateral or bilateral, with corresponding mean ages at diagnosis of 24 months and 12 months, respectively [3]. Without treatment, retinoblastoma is universally fatal secondary to intracranial extension and disseminated disease. Fortunately, advances in diagnosis and treatment have allowed The authors have nothing to disclose.
*Corresponding author. Retina Division, Wilmer Eye Institute, 600 North Wolfe Street, Maumenee 744, Baltimore, MD 21287-9277. E-mail address: [email protected] 2452-1760/16/$ – see front matter http://dx.doi.org/10.1016/j.yaoo.2016.03.010
Ó 2016 Elsevier Inc. All rights reserved.
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for a high control rate (approaching 99% 10-year survival in developed countries) [4]. In addition to improved survival, newer treatments have resulted in an increase in globe salvage and preservation of vision. Treatment modalities widely used in current practice include chemotherapy (intravenous and/or intraarterial), laser thermotherapy, cryotherapy, radioactive plaque brachytherapy, and enucleation for advanced cases. There has been a shift away from the use of external beam radiotherapy. Although effective, radiation has largely been abandoned due to local side effects and the risk of secondary neoplasms within the radiation field. There has been a corresponding increase in the use of chemotherapy and local globe-preserving techniques. In many centers worldwide, systemic (or intravenous) chemotherapy is administered as a 3-drug regimen consisting of carboplatin, etoposide, and vincristine [5]. Intra-arterial chemotherapy is a newer technique by which the chemotherapeutic agent (predominantly melphalan) is delivered directly via the ophthalmic artery, thereby allowing for selective treatment of ocular tumors while minimizing systemic toxicity [6,7]. More recently, intravitreal chemotherapy has shown great promise when used in conjunction with intravenous and/or intra-arterial chemotherapy. One of the greatest challenges in the treatment of retinoblastoma is vitreous seeds. Vitreous seeds consist of clusters of free-floating tumor cells within the vitreous cavity. These cells harbor the potential to proliferate within the vitreous and to implant on the retina and to develop into new tumors. Vitreous seeding is a leading contributor to treatment failure because seeds may persist despite traditional forms of chemotherapy and local treatment. This is due in part to poor penetration of chemotherapeutic agents through the bloodretinal barrier into the vitreous cavity. Intravitreal chemotherapy provides a means for localized drug delivery at high concentrations within the vitreous cavity. Although intravitreal injection was once feared due to the risk of tumor seeding outside the eye, recent evidence has demonstrated that intravitreal therapy is both safe and efficacious when performed carefully, using established protocols. INDICATIONS AND HISTORICAL ASPECTS At present, intravitreal therapy is primarily indicated for patients with vitreous seeds that are unresponsive to standard treatment (intravenous or intra-arterial chemotherapy) or in cases of recurrent vitreous seeding on completion of prior treatment. Early pioneering work in the area of intravitreal chemotherapy using thioTEPA was initiated by Ericson and colleagues [8] in the early 1960s. The rationale for such studies was that rapidly growing, necrotic tumors have a poor blood supply; therefore, chemotherapy delivered through the systemic circulation potentially is less effective. Local delivery of chemotherapeutic agents directly into the eye was an attractive alternative for eradication of tumor cells. Further work investigated intravitreal injection of multiple
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chemotherapeutic agents, including thio-TEPA, nitrogen mustard, cyclophosphamide, and methotrexate in rabbit models [8,9]. Nitrogen mustard was determined to be a toxic preparation, leading to both anterior and posterior segment inflammation and retinal hemorrhage, but several of the other agents were potential candidates for further development. Despite these early investigations, intravitreal chemotherapy was not embraced until many years later, largely due to concerns related to iatrogenic extraocular tumor dissemination. In the late 1980s, the concept of intravitreal therapy was revisited when studies from Japan demonstrated that melphalan was highly effective in the treatment of retinoblastoma [10]. In a series of 264 eyes with vitreous seeding treated with intravitreal melphalan, in doses ranging from 8 lg to 24 lg, 68% of treated eyes achieved complete remission [11]. Optimal dosing of melphalan was subsequently refined. Munier and colleagues [12] studied the use of intravitreal melphalan in doses of 20 lg to 30 lg, administered weekly, in a series of 23 patients with previously treated retinoblastoma and recurrent vitreous seeds. At 15 months’ follow-up, there was an 83% control rate of tumor seeding. This dosing was further supported by studies in which low-dose melphalan (ranging from 8 lg to 10 lg) resulted in only a 42% control rate, whereas higher doses (50 lg) were associated with significant toxicity, including phthisis bulbi [13,14]. THERAPEUTIC AGENTS A majority of series to date have reported on the use of intravitreal melphalan to treat refractory or recurrent vitreous seeds in retinoblastoma. Other chemotherapeutic agents, such as topotecan, combination therapies, and others, have been used to a lesser extent. A brief summary of the intravitreal use of these agents follows. Melphalan Melphalan is a cytotoxic nitrogen mustard derivative alkylating agent that inhibits both DNA and RNA synthesis. It was first used as a treatment of multiple myeloma, melanoma, and ovarian cancer. Its application in retinoblastoma was discovered through in vitro chemosensitivity assays of various anticancer agents and their effects on retinoblastoma cells [15]. Of 12 anticancer drugs investigated, melphalan was found the most effective. Melphalan hydrochloride is commercially available as 50-mg lyophilized powder, which can be reconstituted under sterile conditions with preservative-free 0.9% sodium chloride. A method for compounding melphalan for intravitreal use has previously been described [16]. Briefly, 10 mL of 0.9% preservative-free normal saline is added to melphalan powder to prepare a concentration of 5 mg/1 mL. The mixture is thoroughly agitated until all of the powder is dissolved and the solution is clear. Next, a 1-mL volume of this melphalan solution is injected into an evacuated sterile vial to
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which 24 mL of 0.9% sodium chloride is added, resulting in a solution of 0.2 mg/mL (200 lg/mL). The reconstituted melphalan (0.3 mL) is subsequently transferred to a 1-mL Luer-Lok syringe through a 5-lm filter. The desired dose is obtained by adjusting the volume in the syringe accordingly (20 lg/0.1 mL, 25 lg/0.125 mL, or 30 lg/0.15 mL). An important consideration in using melphalan is that the drug has a short half-life and, therefore, should be administered within 1 hour of mixing in the chemotherapy pharmacy [16]. Topotecan Intravitreal topotecan has been used to a lesser extent, in animal studies, and also in some small series in humans, showing early promising results [17–19]. Topotecan is a topoisomerase inhibitor. It is a synthetic, watersoluble analog of the naturally occurring chemical compound camptothecin, which is a cytotoxic quinoline alkaloid isolated from the tree species Camptotheca acuminata. Topotecan has traditionally been used to treat ovarian cancer, lung cancer, and other cancers, but early work has shown promising results for application in retinoblastoma [17,18]. As with melphalan, topotecan hydrochloride can be reconstituted using sterile 0.9% normal saline to obtain a concentration of 20 lg/0.1 mL. Topotecan has a longer half-life compared with melphalan. This provides certain practical advantages with less rigorous limitations in transport time from the chemotherapy pharmacy to the operating room. Combination therapy Combination treatments (such as intravitreal melphalan and topotecan) may have a synergistic effect and potentially achieve increased tumor control with fewer injections. In 1 small series, a combination of intravitreal topotecan with melphalan led to control of vitreous seeding, requiring only 1 to 3 injections, compared with a more standard 6-injection regimen [18]. In another retrospective interventional case series of 40 consecutive eyes with residual vitreous seeds after standard chemotherapy, sustained local control was achieved with approximately 4 treatments of intravitreal melphalan (20–30 lg) and/or topotecan (20 lg) at 3 years’ follow-up [20]. TECHNIQUE AND SAFETY CONSIDERATIONS Due to the aggressive nature of retinoblastoma and its propensity for orbital dissemination, there are safety considerations that are unique to intravitreal injection of chemotherapy. Standardized techniques with an excellent safety track record have been previously described by several groups [16,21]. Melphalan or other agents should be reconstituted under sterile conditions, ideally in a chemotherapy pharmacy with extensive expertise in handling these chemotherapeutic drugs. Of importance, melphalan is unstable and should be used soon after it is reconstituted. The package insert for melphalan states that after dilution of the reconstituted commercial formulation with sterile saline,
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administration should be completed within 60 minutes [22]. The stability of melphalan specifically for intravitreal use has been investigated. It has been determined that for a 30-lg intravitreal dose, melphalan should administered no more than 2 hours after reconstitution [23]. One center with extensive expertise in intravitreal therapy for retinoblastoma has described their technique, which addresses 5 main parameters that could potentially contribute to extraocular tumor spread [21]. These parameters include number and size of entry wound(s), location of the tumor with respect to the needle entrance site, pressure gradient across the sclera, duration of exposure, and potential spilling of tumor cells along the needle tract. To address these concerns, the investigators suggest several safetyenhancing techniques for intravitreal injection. This begins with performing an anterior chamber paracentesis to decrease intraocular pressure and subsequent likelihood of egress of vitreous fluid with tumor cells after injection. The pars plana injection site is carefully selected in a region free of tumor. Careful inspection of the peripheral retina is accomplished with scleral depression. Furthermore, the assistance of standard B-scan ultrasonography and/or ultrasound biomicroscopy may be used to assess the degree of anterior extension of tumor(s). A fine, generally a 32-gauge or 33-gauge, needle is used for injection and creates an approximately 10-lm entry wound. Ideally, the procedure is performed quickly in an efficient manner. It has been suggested that only 15 seconds are required to perform injection. In this manner, the first 10 seconds are allotted for positioning the needle in the vitreous cavity under microscopic visualization, and then the injection is performed over the remaining 5 seconds. After injection, the needle is withdrawn through an ice ball created with a cryotherapy probe [21]. Modifications to this technique and additional safety measures have also been reported. Such measures include digital massage to lower intraocular pressure (in place of anterior chamber paracentesis), thorough rinsing of the eye with saline after intravitreal injection, and subconjunctival injection of the chemotherapeutic agent at the needle site to eradicate potential tumor cells [24]. EFFICACY OF INTRAVITREAL CHEMOTHERAPY Intravitreal chemotherapy, when combined with systemic and/or intraarterial chemotherapy, has shown early promising results (Figs. 1 and 2). Globe salvage rates of 67% to 100% for retinoblastoma with vitreous seeding have been reported in small, retrospective studies. In 2012, Munier and colleagues [12] reported a series of 23 eyes treated with intravitreal melphalan (122 injections) for persistent vitreous seeding after primary therapy. In this series, intravitreal therapy (20–30 lg of melphalan) was administered every 7 to 10 days. This resulted in globe salvage and complete remission in 20 of 23 eyes (87%) over a median follow-up of 22 months. Complete fragmentation of vitreous seeds or visible response was reported after a median of 4 injections. Subsequent studies have demonstrated similar efficacy of intravitreal therapy. In 2014, Shields and colleagues [25] reported a series of
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Fig. 1. (A) Right eye in a child with retinoblastoma demonstrating diffuse vitreous seeding after 3 (of 6 planned monthly cycles) cycles of intravenous chemotherapy with carboplatin, etoposide, and vincristine. The child was treated with 3 intravitreal injections of melphalan. (B) There was decrease in vitreous seeding and calcification of the remaining seeds. (C) There was reactivation of the main tumor after 6 injections. (D) After 6 cycles of intravenous chemotherapy, local consolidation, and 10 intravitreal injections of melphalan, the main tumor and vitreous seeds demonstrated excellent response to treatment. (Courtesy of Jonathan W. Kim, MD, Director Ocular Oncology, and Jesse L. Berry, MD, Associate Director Ocular Oncology, Children’s Hospital Los Angeles.)
11 eyes with persistent or recurrent vitreous seeding after primary therapy treated with intravitreal melphalan (20–30 lg, injected in a volume of 0.1 mL). Fewer than 6 injections per eye (administered on a monthly schedule) resulted in vitreous seed resolution in 100% of eyes over a median follow-up of 9 months. Subsequently, Ghassemi and colleagues [18], assessed the efficacy of combination intravitreal melphalan and topotecan in 9 eyes with recurrent vitreous seeding after primary therapy and demonstrated that tumor control was achieved after 1 to 3 injections in 6 eyes (67%) over a median follow-up of 16 months.
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Fig. 2. (A) Right eye in a child with retinoblastoma who was treated with intravenous chemotherapy (carboplatin, etoposide, and vincristine) and external beam radiotherapy. Extensive vitreous seeds persisted. (B) After 7 intravitreal injections of melphalan, the vitreous seeds demonstrated excellent regression. (C) Two months after the last melphalan injection there was continued resolution of the granular seeds without further therapy and stable chorioretinal changes. (Courtesy of Jonathan W. Kim, MD, Director Ocular Oncology, and Jesse L. Berry, MD, Associate Director Ocular Oncology, Children’s Hospital Los Angeles.)
The pattern of vitreous seeding is important in predicting response to intravitreal chemotherapy. In 2015, Francis and colleagues [26] described several unique patterns of vitreous seeding in 87 eyes with retinoblastoma. Patterns were classified as ‘‘dust’’ (small granules of vitreous opacities), ‘‘spheres’’ (spherically shaped opacities in the vitreous), or ‘‘clouds’’ (dense collection of punctate vitreous opacities). Eyes with a dust pattern were the most responsive to intravitreal melphalan (median dose of 20 lg) and demonstrated a median time to regression of 2 to 3 weeks after a median of 3 injections (given on a weekly schedule). Eyes with spheres (median dose of 30 lg) required a longer treatment course, with median regression time of 6 to 7 weeks after a median of
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5 injections. Eyes with clouds (median dose of 33 lg) had a median regression time of 30 to 32 weeks after a median of 8 injections. Overall, this cohort had a globe salvage rate of 90.4% after a follow-up of 24 months. SIDE EFFECTS OF INTRAVITREAL CHEMOTHERAPY Although promising when used in conjunction with standard chemotherapy for retinoblastoma, intravitreal chemotherapy does have associated toxicity. Smith and Smith [27] conducted a comprehensive review on the ocular side effects of intravitreal chemotherapy for retinoblastoma. Findings were based on retrospective review of 1287 intravitreal injections, in 306 eyes, of 295 patients, after a mean follow-up of 74.1 months. A majority of patients (88.5%) received melphalan at doses of 8 lg to 30 lg. In total, ocular side effects were noted in 38 patients (12.9%). Serious side effects included iris atrophy, chorioretinal atrophy, vitreous hemorrhage, and retinal detachment. Minor side effects included transiently elevated intraocular pressure, transient vitreous opacities, vitreous condensation, mild vitreous hemorrhage, mild ocular inflammation, corneal edema, transient conjunctivitis, sub-Tenon hemorrhage, mild retinal vasculitis with retinal pigment epithelial abnormalities, transient keratitis, and cataract [27]. Electroretinogram has also been used to assess retinal toxicity after intravitreal chemotherapy. In 1 series of 16 eyes that collectively underwent 107 weekly intravitreal injections of 30 lg of melphalan, decreased electroretinogram responses were observed after successive injections. Electroretinogram amplitudes decreased by 5.8 lV for every additional injection [28]. Because intravitreal chemotherapy has recently been introduced, potential long-term side effects are not yet known. SAFETY CONSIDERATIONS The most feared complication of intravitreal chemotherapy for retinoblastoma is tumor seeding leading to extraocular spread. As with all intraocular procedures, intravitreal injection poses a theoretic risk of reflux of tumors cells and subsequent tumor dissemination. Adding to concerns is that retinoblastoma is an aggressive, poorly cohesive tumor and is prone to seeding. Histopathologic studies have demonstrated that tumor seeding of the needle tract is an observed phenomenon. In 1 series of fine-needle aspiration biopsies performed on 4 globes (3 of which contained retinoblastoma), histologic sections demonstrated tumor cells in 6 of 11 needle tracts [29]. The literature contains numerous case reports of eyes that underwent intraocular surgery (in particular vitrectomy) and biopsy of unsuspected retinoblastoma that resulted in subsequent orbital dissemination [30]. Topotecan fluoresces when exposed to ultraviolet light, thereby making it possible to study some of the effects of periocular and intraocular delivery of this chemotherapeutic agent. In particular, this property has been exploited to study the effects after injection of topotecan into the subconjunctival space and vitreous cavity [31]. Using a Wood lamp, it has been shown that topotecan
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can exhibit retrograde flow through the needle tract, spillage into the tear film, and leakage onto the eyelid and periocular skin. Chemotherapeutic agents are potentially toxic to the dermis and may result in symptomatic consequences after exposure. Irrigation of contaminated skin with balanced salt solution to limit exposure to the drug may be beneficial when using topotecan. Fortunately, with modern intravitreal injection techniques and additional safety precautions, intravitreal chemotherapy has thus far been shown both efficacious and safe. A large series evaluated safety after 135 intravitreal injections (ranging from 1–10 injections per patient) in 30 children with retinoblastoma. The injected medicines included carboplatin, melphalan, or ranibizumab. No cases of extraocular recurrence or systemic spread were observed over a 13.5-month follow-up period (range 1–66 months). Five eyes were ultimately enucleated and on histopathologic examination, none of the needle tracks contained tumor cells [21]. Similarly, a large systematic review evaluated rates of tumor dissemination in eyes with retinoblastoma treated with intravitreal injection. Fourteen studies, comprising 1304 intravitreal injections in 315 eyes of 304 patients, were reviewed. The average follow-up time was 72 months. In this large series, there was only 1 report of extraocular tumor spread and 1 other individual in whom intravitreal therapy could not be excluded as a contributor to metastatic disease. In a subgroup analysis of 61 individuals, intravitreal injections were administered using the previously described safetyenhancing techniques, and there were no reported cases of metastases in this cohort after a mean follow-up of 19 months [27]. Another potential concern regarding the use of intravitreal chemotherapy for retinoblastoma is that it may potentially mask high-risk features (for example, massive choroidal invasion or optic nerve involvement) in eyes that may have otherwise been enucleated. In a patient with advanced disease who initially responds well to systemic and/or intra-arterial chemotherapy combined with intravitreal chemotherapy, delayed recurrence, extraocular spread, and higher risk of metastasis are theoretic concerns. Fortunately, early studies have not demonstrated an increased risk of these adverse events [27]. RELEVANCE TO CURRENT TREATMENT OF RETINOBLASTOMA Recent advances, in particular, the introduction of intra-arterial and, more recently, intravitreal chemotherapy, have revolutionized the care of retinoblastoma in recent years. There has been a trend toward globe preservation and retention of visual acuity in eyes that previously might have been destined for enucleation. Vitreous seeding remains a challenge in the treatment of retinoblastoma, and it is in such cases that intravitreal chemotherapy holds great promise as an adjuvant therapy when combined with standard treatments. As previously discussed, there is evidence that intravitreal chemotherapy can result in treatment response and globe salvage in more than two-thirds of eyes with persistent vitreous seeding after intravenous and/or intra-arterial chemotherapy [12,18,25]. Although globe salvage rates are increasing with the advent of intravitreal chemotherapy, visual acuity outcomes have not
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been extensively examined. Most series published to date focus on disease control and globe salvage; therefore, the impact of intravitreal therapy on visual function warrants further attention. LIMITATIONS Despite treatment with intravenous and/or intra-arterial chemotherapy combined with adjuvant intravitreal chemotherapy, some eyes ultimately require enucleation. In a recent series, among 87 eyes treated with intravitreal chemotherapy, 6.9% still required enucleation after 2 years’ follow-up [26]. Smaller series have demonstrated that 0% to 33% of eyes require enucleation after treatment with intravitreal chemotherapy [12,18,25]. Importantly, in all of these studies, there has not been a single case of death from extraocular tumor extension after follow-up periods ranging from 7 to 86 months. CONTRAINDICATIONS Although promising as an adjuvant, localized form of chemotherapy for retinoblastoma, intravitreal chemotherapy is not appropriate in all cases. To reduce the risk of extraocular tumor extension and iatrogenic complications, there are guidelines relevant to intravitreal injections. A thorough scleral depressed examination of the retinal periphery as well as ultrasonography (B-scan ultrasonography, ultrasound biomicroscopy, or both) should be performed prior to injection, to enhance safety. The following features have been suggested as contraindications (in most cases) to performing intravitreal injection of chemotherapy: 1. 2. 3. 4. 5. 6.
Presence Presence Presence Presence Presence Presence
of of of of of of
anterior segment, posterior chamber, or ciliary body invasion secondary glaucoma hyaloid detachment retinal detachment at the needle entry site tumor or vitreous seeds at the needle entry site dense vitreous hemorrhage
FUTURE DIRECTIONS Future prospective, randomized, clinical trials would ideally refine understanding of the safest and most efficacious regimen of intravitreal chemotherapy. Because retinoblastoma is a rare condition with a wide spectrum of disease severity, it is difficult to establish such trials from practical and feasibility standpoints. An international consortium for retinoblastoma may be beneficial for pooling collective experience and designing multicenter clinical trials. Several aspects of intravitreal chemotherapy warrant further investigation. These include selection of the optimal chemotherapeutic agent, concentration/dose, and frequency of administration. At present, intravitreal chemotherapy is commonly performed on a weekly basis in many oncology centers worldwide. This requires multiple and frequent visits to the operating room as well as repeated administration of general anesthesia in the pediatric
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population. The development of a new intravitreal chemotherapeutic agent with a sustained duration of action could potentially reduce the number and frequency of invasive injection procedures. Furthermore, the best surgical technique for intravitreal injections needs to be determined. Although several groups have reported on their treatment success rates and safety outcomes, these are generally small series with variable follow-up. Currently, the role of intravitreal chemotherapy is predominantly as an adjuvant therapy for vitreous seeding refractory to primary treatment. In the future, it may prove effective for additional indications. In 1 small series, 3 eyes of 3 patients received a median of 7 weekly intravitreal melphalan injections (30 lg of melphalan, injected in a volume of 0.07 mL) for persistent retinal or subretinal tumor refractory to treatment with multiple-course intra-arterial chemotherapy. Eyes were tumor-free at 14 months’ follow-up, demonstrating that nonvitreous disease refractory to primary therapy can regress with intravitreal melphalan [32]. As chemotherapeutic agents evolve, it may even be possible to replace local therapies, such as cryotherapy and laser therapy, with intravitreal therapy. In the future, intravitreal chemotherapy may potentially play a role as primary therapy for retinoblastoma. Adenoviral vectors A phase 1 study demonstrated the safety of intravitreal injection of an adenoviral vector containing a herpes simplex thymidine kinase gene (AdVTK) followed by systemic ganciclovir for treatment of bilateral retinoblastoma unresponsive to standard treatment. Eight patients were enrolled in the study. Vitreous seeds were treated by intravitreous injection of AdV-TK adjacent to disease sites. Each injection was followed by ganciclovir delivered intravenously every 12 hours for 7 days. One patient treated with a lower dose (108 viral particles) had resolution of vitreous seeds at the injection site. The remaining 7 patients, treated with a higher dose (doses 1010), had complete resolution of vitreous seeds and 1 patient remained free of active vitreous seeds 38 months after treatment. Side effects included mild to moderate ocular inflammation, corneal edema, and elevated intraocular pressure. None of the patients had extraocular spread of tumor along the needle tract [33]. The strategy of intravitreal delivery of suicide gene therapy may play a future role in the treatment of children with retinoblastoma with vitreous seeds; however, further work in this area is needed. SUMMARY In recent years, major advances in the delivery of chemotherapy for the treatment of retinoblastoma have resulted in higher rates of globe salvage as well as preservation of vision in many cases. Among these advances, intravitreal chemotherapy has shown great promise as an adjuvant therapy for vitreous seeding refractory to standard systemic and/or intra-arterial chemotherapy. Intravitreal chemotherapy has now gained international acceptance and is considered a safe and effective technique when performed appropriately for select
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cases. There are unique safety considerations when performing intravitreal injection in eyes with retinoblastoma, and, therefore, care should be taken to follow previously established protocols. In the future, there is potential to develop newer chemotherapeutic agents with improved efficacy to decrease the number and frequency of injections. Furthermore, future work may focus on the development of intravitreal therapies with an improved side-effect profile. References [1] Broaddus E, Topham A, Singh AD. Survival with retinoblastoma in the United States: 19752004. Br J Ophthalmol 2008;93(1):24–7. [2] Abramson DH, Frank CM, Susman M, et al. Presenting signs of retinoblastoma. J Pediatr 1998;132(3):505–8. [3] Ries LAG, Smith MA, Gurney JG, et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda (USA): National Cancer Institute (NCI); 1999. [4] Tamboli D, Topham A, Singh N, et al. Retinoblastoma: a SEER dataset evaluation for treatment patterns, survival, and second malignant neoplasms. Am J Ophthalmol 2015;160(5):953–8. [5] Childrens Oncology Group. Available at: http://www.childrensoncologygroup.org/. Accessed February 24, 2016. [6] Jabbour P, Chalouhi N, Tjoumakaris S, et al. Pearls and pitfalls of intraarterial chemotherapy for retinoblastoma: a review. J Neurosurg Pediatr 2012;10(3):175–81. [7] Abramson DH. Retinoblastoma: saving life with vision. Annu Rev Med 2014;65:171–84. [8] Ericson L, Karlberg B, Rosengren BHO. Trials of intravitreal injections of chemotherapeutic agents in rabbits. Acta Ophthalmol 1964;42(4):721–6. [9] Kivela ¨ T, Eskelin S, Paloheimo M. Intravitreal methotrexate for retinoblastoma. Ophthalmology 2011;118(8):1689. [10] Inomata M, Kaneko A. Chemosensitivity profiles of primary and cultured human retinoblastoma cells in a human tumor clonogenic assay. Jpn J Cancer Res 1987;78(8):858–68. [11] Suzuki S, Aihara Y, Fujiwara M, et al. Intravitreal injection of melphalan for intraocular retinoblastoma. Jpn J Ophthalmol 2015;59(3):164–72. [12] Munier FL, Gaillard M-C, Balmer A, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol 2012;96(8):1078–83. [13] Ghassemi F, Shields CL. Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol 2012;130(10):1268–71. [14] Ghassemi F, Amoli FA. Pathological findings in enucleated eyes after intravitreal melphalan injection. Int Ophthalmol 2014;34(3):533–40. [15] Inomata M, Kaneko A. In vitro chemosensitivity assays of retinoblastoma cells. Int J Clin Oncol 2004;9(1):31–5. [16] Manjandavida FP, Shields CL. The role of intravitreal chemotherapy for retinoblastoma. Indian J Ophthalmol 2015;63(2):141. [17] Buitrago E, Del Sole MJ, Torbidoni A, et al. Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma. Exp Eye Res 2013;108:103–9. [18] Ghassemi F, Shields CL, Ghadimi H, et al. Combined intravitreal melphalan and topotecan for refractory or recurrent vitreous seeding from retinoblastoma. JAMA Ophthalmol 2014;132(8):936–41. [19] Schaiquevich P, Carcaboso AM, Buitrago E, et al. Ocular pharmacology of topotecan and its activity in retinoblastoma. Retina 2014;34(9):1719–27. [20] Shields CL, Douglass AM, Beggache M, et al. INTRAVITREOUS CHEMOTHERAPY FOR ACTIVE VITREOUS SEEDING FROM RETINOBLASTOMA: outcomes after 192 consecutive injections. The 2015 Howard Naquin Lecture. Retina 2016;36(6):1184–90.
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[21] Munier FL, Soliman S, Moulin AP, et al. Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilisation of the needle track. Br J Ophthalmol 2012;96(8):1084–7. [22] ÓYEAR G. ALKERANÒ (melphalan hydrochloride) for Injection; PRESCRIBING INFORMATION. Glaxosmith Kline 2007. [23] Buitrago E, Lagomarsino E, Mato G, et al. Stability of Melphalan Solution for Intravitreal Injection for Retinoblastoma. JAMA Ophthalmol 2014;132(11):1372–3. [24] Smith SJ, Pulido JS, Saloma ˜ o DR, et al. Combined intravitreal and subconjunctival carboplatin for retinoblastoma with vitreous seeds. Br J Ophthalmol 2012;96(8):1073–7. [25] Shields CL, Manjandavida FP, Arepalli S, et al. Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results. JAMA Ophthalmol 2014;132(3): 319–25. [26] Francis JH, Abramson DH, Gaillard MC, et al. The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan. Ophthalmology 2015;122(6):1173–9. [27] Smith SJ, Smith BD. Evaluating the risk of extraocular tumour spread following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol 2013;97(10): 1231–6. [28] Francis JH, Schaiquevich P, Buitrago E, et al. Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study. Ophthalmology 2014;121(9):1810–7. [29] Karcioglu ZA, Gordon RA, Karcioglu GL. Tumor seeding in ocular fine needle aspiration biopsy. Ophthalmology 1985;92(12):1763–7. [30] Shields CL, Honavar S, Shields JA, et al. Vitrectomy in eyes with unsuspected retinoblastoma. Ophthalmology 2000;107(12):2250–5. [31] Francis JH, Marr BP, Schaiquevich P, et al. Properties and clinical utility of topotecan fluorescence: uses for retinoblastoma. Br J Ophthalmol 2015;99(10):1320–2. [32] Francis JH, Marr BP, Brodie SE, et al. Intravitreal melphalan as salvage therapy for refractory retinal and subretinal retinoblastoma. Retin Cases Brief Rep 2015;1–4. [33] Che´vez-Barrios P, Chintagumpala M, Mieler W, et al. Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir. J Clin Oncol 2005;23(31):7927–35.
ADVANCES IN OPHTHALMOLOGY AND OPTOMETRY
Intravitreal Chemotherapy for Retinoblastoma Roomasa Channa, MD, Jithin Yohannan, MD, Mary Aronow, MD* Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA
Keywords
Retinoblastoma Intravitreal chemotherapy Melphalan Vitreous seeds
Key points
Intravitreal chemotherapy is a promising therapy when used in conjunction with systemic and/or intra-arterial chemotherapy for the treatment of retinoblastoma associated with vitreous seeding.
Intravitreal chemotherapy has been shown effective and safe when used in the appropriate setting.
There are several unique safety considerations regarding the administration of chemotherapy by intravitreal injection for the treatment of retinoblastoma.
INTRODUCTION Retinoblastoma is the most common pediatric intraocular malignancy. The age-adjusted incidence is 11.8 cases per million children, which in the United States translates to approximately 300 new cases annually [1]. Retinoblastoma results from either somatic or germline mutations within RB1, a tumor suppressor gene, located on the long arm of chromosome 13 at region 14. Children most frequently present with leukokoria (or a white pupil reflex) [2]. Involvement may be unilateral or bilateral, with corresponding mean ages at diagnosis of 24 months and 12 months, respectively [3]. Without treatment, retinoblastoma is universally fatal secondary to intracranial extension and disseminated disease. Fortunately, advances in diagnosis and treatment have allowed The authors have nothing to disclose.
*Corresponding author. Retina Division, Wilmer Eye Institute, 600 North Wolfe Street, Maumenee 744, Baltimore, MD 21287-9277. E-mail address: [email protected] 2452-1760/16/$ – see front matter http://dx.doi.org/10.1016/j.yaoo.2016.03.010
Ó 2016 Elsevier Inc. All rights reserved.
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for a high control rate (approaching 99% 10-year survival in developed countries) [4]. In addition to improved survival, newer treatments have resulted in an increase in globe salvage and preservation of vision. Treatment modalities widely used in current practice include chemotherapy (intravenous and/or intraarterial), laser thermotherapy, cryotherapy, radioactive plaque brachytherapy, and enucleation for advanced cases. There has been a shift away from the use of external beam radiotherapy. Although effective, radiation has largely been abandoned due to local side effects and the risk of secondary neoplasms within the radiation field. There has been a corresponding increase in the use of chemotherapy and local globe-preserving techniques. In many centers worldwide, systemic (or intravenous) chemotherapy is administered as a 3-drug regimen consisting of carboplatin, etoposide, and vincristine [5]. Intra-arterial chemotherapy is a newer technique by which the chemotherapeutic agent (predominantly melphalan) is delivered directly via the ophthalmic artery, thereby allowing for selective treatment of ocular tumors while minimizing systemic toxicity [6,7]. More recently, intravitreal chemotherapy has shown great promise when used in conjunction with intravenous and/or intra-arterial chemotherapy. One of the greatest challenges in the treatment of retinoblastoma is vitreous seeds. Vitreous seeds consist of clusters of free-floating tumor cells within the vitreous cavity. These cells harbor the potential to proliferate within the vitreous and to implant on the retina and to develop into new tumors. Vitreous seeding is a leading contributor to treatment failure because seeds may persist despite traditional forms of chemotherapy and local treatment. This is due in part to poor penetration of chemotherapeutic agents through the bloodretinal barrier into the vitreous cavity. Intravitreal chemotherapy provides a means for localized drug delivery at high concentrations within the vitreous cavity. Although intravitreal injection was once feared due to the risk of tumor seeding outside the eye, recent evidence has demonstrated that intravitreal therapy is both safe and efficacious when performed carefully, using established protocols. INDICATIONS AND HISTORICAL ASPECTS At present, intravitreal therapy is primarily indicated for patients with vitreous seeds that are unresponsive to standard treatment (intravenous or intra-arterial chemotherapy) or in cases of recurrent vitreous seeding on completion of prior treatment. Early pioneering work in the area of intravitreal chemotherapy using thioTEPA was initiated by Ericson and colleagues [8] in the early 1960s. The rationale for such studies was that rapidly growing, necrotic tumors have a poor blood supply; therefore, chemotherapy delivered through the systemic circulation potentially is less effective. Local delivery of chemotherapeutic agents directly into the eye was an attractive alternative for eradication of tumor cells. Further work investigated intravitreal injection of multiple
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chemotherapeutic agents, including thio-TEPA, nitrogen mustard, cyclophosphamide, and methotrexate in rabbit models [8,9]. Nitrogen mustard was determined to be a toxic preparation, leading to both anterior and posterior segment inflammation and retinal hemorrhage, but several of the other agents were potential candidates for further development. Despite these early investigations, intravitreal chemotherapy was not embraced until many years later, largely due to concerns related to iatrogenic extraocular tumor dissemination. In the late 1980s, the concept of intravitreal therapy was revisited when studies from Japan demonstrated that melphalan was highly effective in the treatment of retinoblastoma [10]. In a series of 264 eyes with vitreous seeding treated with intravitreal melphalan, in doses ranging from 8 lg to 24 lg, 68% of treated eyes achieved complete remission [11]. Optimal dosing of melphalan was subsequently refined. Munier and colleagues [12] studied the use of intravitreal melphalan in doses of 20 lg to 30 lg, administered weekly, in a series of 23 patients with previously treated retinoblastoma and recurrent vitreous seeds. At 15 months’ follow-up, there was an 83% control rate of tumor seeding. This dosing was further supported by studies in which low-dose melphalan (ranging from 8 lg to 10 lg) resulted in only a 42% control rate, whereas higher doses (50 lg) were associated with significant toxicity, including phthisis bulbi [13,14]. THERAPEUTIC AGENTS A majority of series to date have reported on the use of intravitreal melphalan to treat refractory or recurrent vitreous seeds in retinoblastoma. Other chemotherapeutic agents, such as topotecan, combination therapies, and others, have been used to a lesser extent. A brief summary of the intravitreal use of these agents follows. Melphalan Melphalan is a cytotoxic nitrogen mustard derivative alkylating agent that inhibits both DNA and RNA synthesis. It was first used as a treatment of multiple myeloma, melanoma, and ovarian cancer. Its application in retinoblastoma was discovered through in vitro chemosensitivity assays of various anticancer agents and their effects on retinoblastoma cells [15]. Of 12 anticancer drugs investigated, melphalan was found the most effective. Melphalan hydrochloride is commercially available as 50-mg lyophilized powder, which can be reconstituted under sterile conditions with preservative-free 0.9% sodium chloride. A method for compounding melphalan for intravitreal use has previously been described [16]. Briefly, 10 mL of 0.9% preservative-free normal saline is added to melphalan powder to prepare a concentration of 5 mg/1 mL. The mixture is thoroughly agitated until all of the powder is dissolved and the solution is clear. Next, a 1-mL volume of this melphalan solution is injected into an evacuated sterile vial to
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which 24 mL of 0.9% sodium chloride is added, resulting in a solution of 0.2 mg/mL (200 lg/mL). The reconstituted melphalan (0.3 mL) is subsequently transferred to a 1-mL Luer-Lok syringe through a 5-lm filter. The desired dose is obtained by adjusting the volume in the syringe accordingly (20 lg/0.1 mL, 25 lg/0.125 mL, or 30 lg/0.15 mL). An important consideration in using melphalan is that the drug has a short half-life and, therefore, should be administered within 1 hour of mixing in the chemotherapy pharmacy [16]. Topotecan Intravitreal topotecan has been used to a lesser extent, in animal studies, and also in some small series in humans, showing early promising results [17–19]. Topotecan is a topoisomerase inhibitor. It is a synthetic, watersoluble analog of the naturally occurring chemical compound camptothecin, which is a cytotoxic quinoline alkaloid isolated from the tree species Camptotheca acuminata. Topotecan has traditionally been used to treat ovarian cancer, lung cancer, and other cancers, but early work has shown promising results for application in retinoblastoma [17,18]. As with melphalan, topotecan hydrochloride can be reconstituted using sterile 0.9% normal saline to obtain a concentration of 20 lg/0.1 mL. Topotecan has a longer half-life compared with melphalan. This provides certain practical advantages with less rigorous limitations in transport time from the chemotherapy pharmacy to the operating room. Combination therapy Combination treatments (such as intravitreal melphalan and topotecan) may have a synergistic effect and potentially achieve increased tumor control with fewer injections. In 1 small series, a combination of intravitreal topotecan with melphalan led to control of vitreous seeding, requiring only 1 to 3 injections, compared with a more standard 6-injection regimen [18]. In another retrospective interventional case series of 40 consecutive eyes with residual vitreous seeds after standard chemotherapy, sustained local control was achieved with approximately 4 treatments of intravitreal melphalan (20–30 lg) and/or topotecan (20 lg) at 3 years’ follow-up [20]. TECHNIQUE AND SAFETY CONSIDERATIONS Due to the aggressive nature of retinoblastoma and its propensity for orbital dissemination, there are safety considerations that are unique to intravitreal injection of chemotherapy. Standardized techniques with an excellent safety track record have been previously described by several groups [16,21]. Melphalan or other agents should be reconstituted under sterile conditions, ideally in a chemotherapy pharmacy with extensive expertise in handling these chemotherapeutic drugs. Of importance, melphalan is unstable and should be used soon after it is reconstituted. The package insert for melphalan states that after dilution of the reconstituted commercial formulation with sterile saline,
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administration should be completed within 60 minutes [22]. The stability of melphalan specifically for intravitreal use has been investigated. It has been determined that for a 30-lg intravitreal dose, melphalan should administered no more than 2 hours after reconstitution [23]. One center with extensive expertise in intravitreal therapy for retinoblastoma has described their technique, which addresses 5 main parameters that could potentially contribute to extraocular tumor spread [21]. These parameters include number and size of entry wound(s), location of the tumor with respect to the needle entrance site, pressure gradient across the sclera, duration of exposure, and potential spilling of tumor cells along the needle tract. To address these concerns, the investigators suggest several safetyenhancing techniques for intravitreal injection. This begins with performing an anterior chamber paracentesis to decrease intraocular pressure and subsequent likelihood of egress of vitreous fluid with tumor cells after injection. The pars plana injection site is carefully selected in a region free of tumor. Careful inspection of the peripheral retina is accomplished with scleral depression. Furthermore, the assistance of standard B-scan ultrasonography and/or ultrasound biomicroscopy may be used to assess the degree of anterior extension of tumor(s). A fine, generally a 32-gauge or 33-gauge, needle is used for injection and creates an approximately 10-lm entry wound. Ideally, the procedure is performed quickly in an efficient manner. It has been suggested that only 15 seconds are required to perform injection. In this manner, the first 10 seconds are allotted for positioning the needle in the vitreous cavity under microscopic visualization, and then the injection is performed over the remaining 5 seconds. After injection, the needle is withdrawn through an ice ball created with a cryotherapy probe [21]. Modifications to this technique and additional safety measures have also been reported. Such measures include digital massage to lower intraocular pressure (in place of anterior chamber paracentesis), thorough rinsing of the eye with saline after intravitreal injection, and subconjunctival injection of the chemotherapeutic agent at the needle site to eradicate potential tumor cells [24]. EFFICACY OF INTRAVITREAL CHEMOTHERAPY Intravitreal chemotherapy, when combined with systemic and/or intraarterial chemotherapy, has shown early promising results (Figs. 1 and 2). Globe salvage rates of 67% to 100% for retinoblastoma with vitreous seeding have been reported in small, retrospective studies. In 2012, Munier and colleagues [12] reported a series of 23 eyes treated with intravitreal melphalan (122 injections) for persistent vitreous seeding after primary therapy. In this series, intravitreal therapy (20–30 lg of melphalan) was administered every 7 to 10 days. This resulted in globe salvage and complete remission in 20 of 23 eyes (87%) over a median follow-up of 22 months. Complete fragmentation of vitreous seeds or visible response was reported after a median of 4 injections. Subsequent studies have demonstrated similar efficacy of intravitreal therapy. In 2014, Shields and colleagues [25] reported a series of
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Fig. 1. (A) Right eye in a child with retinoblastoma demonstrating diffuse vitreous seeding after 3 (of 6 planned monthly cycles) cycles of intravenous chemotherapy with carboplatin, etoposide, and vincristine. The child was treated with 3 intravitreal injections of melphalan. (B) There was decrease in vitreous seeding and calcification of the remaining seeds. (C) There was reactivation of the main tumor after 6 injections. (D) After 6 cycles of intravenous chemotherapy, local consolidation, and 10 intravitreal injections of melphalan, the main tumor and vitreous seeds demonstrated excellent response to treatment. (Courtesy of Jonathan W. Kim, MD, Director Ocular Oncology, and Jesse L. Berry, MD, Associate Director Ocular Oncology, Children’s Hospital Los Angeles.)
11 eyes with persistent or recurrent vitreous seeding after primary therapy treated with intravitreal melphalan (20–30 lg, injected in a volume of 0.1 mL). Fewer than 6 injections per eye (administered on a monthly schedule) resulted in vitreous seed resolution in 100% of eyes over a median follow-up of 9 months. Subsequently, Ghassemi and colleagues [18], assessed the efficacy of combination intravitreal melphalan and topotecan in 9 eyes with recurrent vitreous seeding after primary therapy and demonstrated that tumor control was achieved after 1 to 3 injections in 6 eyes (67%) over a median follow-up of 16 months.
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Fig. 2. (A) Right eye in a child with retinoblastoma who was treated with intravenous chemotherapy (carboplatin, etoposide, and vincristine) and external beam radiotherapy. Extensive vitreous seeds persisted. (B) After 7 intravitreal injections of melphalan, the vitreous seeds demonstrated excellent regression. (C) Two months after the last melphalan injection there was continued resolution of the granular seeds without further therapy and stable chorioretinal changes. (Courtesy of Jonathan W. Kim, MD, Director Ocular Oncology, and Jesse L. Berry, MD, Associate Director Ocular Oncology, Children’s Hospital Los Angeles.)
The pattern of vitreous seeding is important in predicting response to intravitreal chemotherapy. In 2015, Francis and colleagues [26] described several unique patterns of vitreous seeding in 87 eyes with retinoblastoma. Patterns were classified as ‘‘dust’’ (small granules of vitreous opacities), ‘‘spheres’’ (spherically shaped opacities in the vitreous), or ‘‘clouds’’ (dense collection of punctate vitreous opacities). Eyes with a dust pattern were the most responsive to intravitreal melphalan (median dose of 20 lg) and demonstrated a median time to regression of 2 to 3 weeks after a median of 3 injections (given on a weekly schedule). Eyes with spheres (median dose of 30 lg) required a longer treatment course, with median regression time of 6 to 7 weeks after a median of
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5 injections. Eyes with clouds (median dose of 33 lg) had a median regression time of 30 to 32 weeks after a median of 8 injections. Overall, this cohort had a globe salvage rate of 90.4% after a follow-up of 24 months. SIDE EFFECTS OF INTRAVITREAL CHEMOTHERAPY Although promising when used in conjunction with standard chemotherapy for retinoblastoma, intravitreal chemotherapy does have associated toxicity. Smith and Smith [27] conducted a comprehensive review on the ocular side effects of intravitreal chemotherapy for retinoblastoma. Findings were based on retrospective review of 1287 intravitreal injections, in 306 eyes, of 295 patients, after a mean follow-up of 74.1 months. A majority of patients (88.5%) received melphalan at doses of 8 lg to 30 lg. In total, ocular side effects were noted in 38 patients (12.9%). Serious side effects included iris atrophy, chorioretinal atrophy, vitreous hemorrhage, and retinal detachment. Minor side effects included transiently elevated intraocular pressure, transient vitreous opacities, vitreous condensation, mild vitreous hemorrhage, mild ocular inflammation, corneal edema, transient conjunctivitis, sub-Tenon hemorrhage, mild retinal vasculitis with retinal pigment epithelial abnormalities, transient keratitis, and cataract [27]. Electroretinogram has also been used to assess retinal toxicity after intravitreal chemotherapy. In 1 series of 16 eyes that collectively underwent 107 weekly intravitreal injections of 30 lg of melphalan, decreased electroretinogram responses were observed after successive injections. Electroretinogram amplitudes decreased by 5.8 lV for every additional injection [28]. Because intravitreal chemotherapy has recently been introduced, potential long-term side effects are not yet known. SAFETY CONSIDERATIONS The most feared complication of intravitreal chemotherapy for retinoblastoma is tumor seeding leading to extraocular spread. As with all intraocular procedures, intravitreal injection poses a theoretic risk of reflux of tumors cells and subsequent tumor dissemination. Adding to concerns is that retinoblastoma is an aggressive, poorly cohesive tumor and is prone to seeding. Histopathologic studies have demonstrated that tumor seeding of the needle tract is an observed phenomenon. In 1 series of fine-needle aspiration biopsies performed on 4 globes (3 of which contained retinoblastoma), histologic sections demonstrated tumor cells in 6 of 11 needle tracts [29]. The literature contains numerous case reports of eyes that underwent intraocular surgery (in particular vitrectomy) and biopsy of unsuspected retinoblastoma that resulted in subsequent orbital dissemination [30]. Topotecan fluoresces when exposed to ultraviolet light, thereby making it possible to study some of the effects of periocular and intraocular delivery of this chemotherapeutic agent. In particular, this property has been exploited to study the effects after injection of topotecan into the subconjunctival space and vitreous cavity [31]. Using a Wood lamp, it has been shown that topotecan
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can exhibit retrograde flow through the needle tract, spillage into the tear film, and leakage onto the eyelid and periocular skin. Chemotherapeutic agents are potentially toxic to the dermis and may result in symptomatic consequences after exposure. Irrigation of contaminated skin with balanced salt solution to limit exposure to the drug may be beneficial when using topotecan. Fortunately, with modern intravitreal injection techniques and additional safety precautions, intravitreal chemotherapy has thus far been shown both efficacious and safe. A large series evaluated safety after 135 intravitreal injections (ranging from 1–10 injections per patient) in 30 children with retinoblastoma. The injected medicines included carboplatin, melphalan, or ranibizumab. No cases of extraocular recurrence or systemic spread were observed over a 13.5-month follow-up period (range 1–66 months). Five eyes were ultimately enucleated and on histopathologic examination, none of the needle tracks contained tumor cells [21]. Similarly, a large systematic review evaluated rates of tumor dissemination in eyes with retinoblastoma treated with intravitreal injection. Fourteen studies, comprising 1304 intravitreal injections in 315 eyes of 304 patients, were reviewed. The average follow-up time was 72 months. In this large series, there was only 1 report of extraocular tumor spread and 1 other individual in whom intravitreal therapy could not be excluded as a contributor to metastatic disease. In a subgroup analysis of 61 individuals, intravitreal injections were administered using the previously described safetyenhancing techniques, and there were no reported cases of metastases in this cohort after a mean follow-up of 19 months [27]. Another potential concern regarding the use of intravitreal chemotherapy for retinoblastoma is that it may potentially mask high-risk features (for example, massive choroidal invasion or optic nerve involvement) in eyes that may have otherwise been enucleated. In a patient with advanced disease who initially responds well to systemic and/or intra-arterial chemotherapy combined with intravitreal chemotherapy, delayed recurrence, extraocular spread, and higher risk of metastasis are theoretic concerns. Fortunately, early studies have not demonstrated an increased risk of these adverse events [27]. RELEVANCE TO CURRENT TREATMENT OF RETINOBLASTOMA Recent advances, in particular, the introduction of intra-arterial and, more recently, intravitreal chemotherapy, have revolutionized the care of retinoblastoma in recent years. There has been a trend toward globe preservation and retention of visual acuity in eyes that previously might have been destined for enucleation. Vitreous seeding remains a challenge in the treatment of retinoblastoma, and it is in such cases that intravitreal chemotherapy holds great promise as an adjuvant therapy when combined with standard treatments. As previously discussed, there is evidence that intravitreal chemotherapy can result in treatment response and globe salvage in more than two-thirds of eyes with persistent vitreous seeding after intravenous and/or intra-arterial chemotherapy [12,18,25]. Although globe salvage rates are increasing with the advent of intravitreal chemotherapy, visual acuity outcomes have not
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been extensively examined. Most series published to date focus on disease control and globe salvage; therefore, the impact of intravitreal therapy on visual function warrants further attention. LIMITATIONS Despite treatment with intravenous and/or intra-arterial chemotherapy combined with adjuvant intravitreal chemotherapy, some eyes ultimately require enucleation. In a recent series, among 87 eyes treated with intravitreal chemotherapy, 6.9% still required enucleation after 2 years’ follow-up [26]. Smaller series have demonstrated that 0% to 33% of eyes require enucleation after treatment with intravitreal chemotherapy [12,18,25]. Importantly, in all of these studies, there has not been a single case of death from extraocular tumor extension after follow-up periods ranging from 7 to 86 months. CONTRAINDICATIONS Although promising as an adjuvant, localized form of chemotherapy for retinoblastoma, intravitreal chemotherapy is not appropriate in all cases. To reduce the risk of extraocular tumor extension and iatrogenic complications, there are guidelines relevant to intravitreal injections. A thorough scleral depressed examination of the retinal periphery as well as ultrasonography (B-scan ultrasonography, ultrasound biomicroscopy, or both) should be performed prior to injection, to enhance safety. The following features have been suggested as contraindications (in most cases) to performing intravitreal injection of chemotherapy: 1. 2. 3. 4. 5. 6.
Presence Presence Presence Presence Presence Presence
of of of of of of
anterior segment, posterior chamber, or ciliary body invasion secondary glaucoma hyaloid detachment retinal detachment at the needle entry site tumor or vitreous seeds at the needle entry site dense vitreous hemorrhage
FUTURE DIRECTIONS Future prospective, randomized, clinical trials would ideally refine understanding of the safest and most efficacious regimen of intravitreal chemotherapy. Because retinoblastoma is a rare condition with a wide spectrum of disease severity, it is difficult to establish such trials from practical and feasibility standpoints. An international consortium for retinoblastoma may be beneficial for pooling collective experience and designing multicenter clinical trials. Several aspects of intravitreal chemotherapy warrant further investigation. These include selection of the optimal chemotherapeutic agent, concentration/dose, and frequency of administration. At present, intravitreal chemotherapy is commonly performed on a weekly basis in many oncology centers worldwide. This requires multiple and frequent visits to the operating room as well as repeated administration of general anesthesia in the pediatric
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population. The development of a new intravitreal chemotherapeutic agent with a sustained duration of action could potentially reduce the number and frequency of invasive injection procedures. Furthermore, the best surgical technique for intravitreal injections needs to be determined. Although several groups have reported on their treatment success rates and safety outcomes, these are generally small series with variable follow-up. Currently, the role of intravitreal chemotherapy is predominantly as an adjuvant therapy for vitreous seeding refractory to primary treatment. In the future, it may prove effective for additional indications. In 1 small series, 3 eyes of 3 patients received a median of 7 weekly intravitreal melphalan injections (30 lg of melphalan, injected in a volume of 0.07 mL) for persistent retinal or subretinal tumor refractory to treatment with multiple-course intra-arterial chemotherapy. Eyes were tumor-free at 14 months’ follow-up, demonstrating that nonvitreous disease refractory to primary therapy can regress with intravitreal melphalan [32]. As chemotherapeutic agents evolve, it may even be possible to replace local therapies, such as cryotherapy and laser therapy, with intravitreal therapy. In the future, intravitreal chemotherapy may potentially play a role as primary therapy for retinoblastoma. Adenoviral vectors A phase 1 study demonstrated the safety of intravitreal injection of an adenoviral vector containing a herpes simplex thymidine kinase gene (AdVTK) followed by systemic ganciclovir for treatment of bilateral retinoblastoma unresponsive to standard treatment. Eight patients were enrolled in the study. Vitreous seeds were treated by intravitreous injection of AdV-TK adjacent to disease sites. Each injection was followed by ganciclovir delivered intravenously every 12 hours for 7 days. One patient treated with a lower dose (108 viral particles) had resolution of vitreous seeds at the injection site. The remaining 7 patients, treated with a higher dose (doses 1010), had complete resolution of vitreous seeds and 1 patient remained free of active vitreous seeds 38 months after treatment. Side effects included mild to moderate ocular inflammation, corneal edema, and elevated intraocular pressure. None of the patients had extraocular spread of tumor along the needle tract [33]. The strategy of intravitreal delivery of suicide gene therapy may play a future role in the treatment of children with retinoblastoma with vitreous seeds; however, further work in this area is needed. SUMMARY In recent years, major advances in the delivery of chemotherapy for the treatment of retinoblastoma have resulted in higher rates of globe salvage as well as preservation of vision in many cases. Among these advances, intravitreal chemotherapy has shown great promise as an adjuvant therapy for vitreous seeding refractory to standard systemic and/or intra-arterial chemotherapy. Intravitreal chemotherapy has now gained international acceptance and is considered a safe and effective technique when performed appropriately for select
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cases. There are unique safety considerations when performing intravitreal injection in eyes with retinoblastoma, and, therefore, care should be taken to follow previously established protocols. In the future, there is potential to develop newer chemotherapeutic agents with improved efficacy to decrease the number and frequency of injections. Furthermore, future work may focus on the development of intravitreal therapies with an improved side-effect profile. References [1] Broaddus E, Topham A, Singh AD. Survival with retinoblastoma in the United States: 19752004. Br J Ophthalmol 2008;93(1):24–7. [2] Abramson DH, Frank CM, Susman M, et al. Presenting signs of retinoblastoma. J Pediatr 1998;132(3):505–8. [3] Ries LAG, Smith MA, Gurney JG, et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda (USA): National Cancer Institute (NCI); 1999. [4] Tamboli D, Topham A, Singh N, et al. Retinoblastoma: a SEER dataset evaluation for treatment patterns, survival, and second malignant neoplasms. Am J Ophthalmol 2015;160(5):953–8. [5] Childrens Oncology Group. Available at: http://www.childrensoncologygroup.org/. Accessed February 24, 2016. [6] Jabbour P, Chalouhi N, Tjoumakaris S, et al. Pearls and pitfalls of intraarterial chemotherapy for retinoblastoma: a review. J Neurosurg Pediatr 2012;10(3):175–81. [7] Abramson DH. Retinoblastoma: saving life with vision. Annu Rev Med 2014;65:171–84. [8] Ericson L, Karlberg B, Rosengren BHO. Trials of intravitreal injections of chemotherapeutic agents in rabbits. Acta Ophthalmol 1964;42(4):721–6. [9] Kivela ¨ T, Eskelin S, Paloheimo M. Intravitreal methotrexate for retinoblastoma. Ophthalmology 2011;118(8):1689. [10] Inomata M, Kaneko A. Chemosensitivity profiles of primary and cultured human retinoblastoma cells in a human tumor clonogenic assay. Jpn J Cancer Res 1987;78(8):858–68. [11] Suzuki S, Aihara Y, Fujiwara M, et al. Intravitreal injection of melphalan for intraocular retinoblastoma. Jpn J Ophthalmol 2015;59(3):164–72. [12] Munier FL, Gaillard M-C, Balmer A, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol 2012;96(8):1078–83. [13] Ghassemi F, Shields CL. Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol 2012;130(10):1268–71. [14] Ghassemi F, Amoli FA. Pathological findings in enucleated eyes after intravitreal melphalan injection. Int Ophthalmol 2014;34(3):533–40. [15] Inomata M, Kaneko A. In vitro chemosensitivity assays of retinoblastoma cells. Int J Clin Oncol 2004;9(1):31–5. [16] Manjandavida FP, Shields CL. The role of intravitreal chemotherapy for retinoblastoma. Indian J Ophthalmol 2015;63(2):141. [17] Buitrago E, Del Sole MJ, Torbidoni A, et al. Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma. Exp Eye Res 2013;108:103–9. [18] Ghassemi F, Shields CL, Ghadimi H, et al. Combined intravitreal melphalan and topotecan for refractory or recurrent vitreous seeding from retinoblastoma. JAMA Ophthalmol 2014;132(8):936–41. [19] Schaiquevich P, Carcaboso AM, Buitrago E, et al. Ocular pharmacology of topotecan and its activity in retinoblastoma. Retina 2014;34(9):1719–27. [20] Shields CL, Douglass AM, Beggache M, et al. INTRAVITREOUS CHEMOTHERAPY FOR ACTIVE VITREOUS SEEDING FROM RETINOBLASTOMA: outcomes after 192 consecutive injections. The 2015 Howard Naquin Lecture. Retina 2016;36(6):1184–90.
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[21] Munier FL, Soliman S, Moulin AP, et al. Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilisation of the needle track. Br J Ophthalmol 2012;96(8):1084–7. [22] ÓYEAR G. ALKERANÒ (melphalan hydrochloride) for Injection; PRESCRIBING INFORMATION. Glaxosmith Kline 2007. [23] Buitrago E, Lagomarsino E, Mato G, et al. Stability of Melphalan Solution for Intravitreal Injection for Retinoblastoma. JAMA Ophthalmol 2014;132(11):1372–3. [24] Smith SJ, Pulido JS, Saloma ˜ o DR, et al. Combined intravitreal and subconjunctival carboplatin for retinoblastoma with vitreous seeds. Br J Ophthalmol 2012;96(8):1073–7. [25] Shields CL, Manjandavida FP, Arepalli S, et al. Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results. JAMA Ophthalmol 2014;132(3): 319–25. [26] Francis JH, Abramson DH, Gaillard MC, et al. The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan. Ophthalmology 2015;122(6):1173–9. [27] Smith SJ, Smith BD. Evaluating the risk of extraocular tumour spread following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol 2013;97(10): 1231–6. [28] Francis JH, Schaiquevich P, Buitrago E, et al. Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study. Ophthalmology 2014;121(9):1810–7. [29] Karcioglu ZA, Gordon RA, Karcioglu GL. Tumor seeding in ocular fine needle aspiration biopsy. Ophthalmology 1985;92(12):1763–7. [30] Shields CL, Honavar S, Shields JA, et al. Vitrectomy in eyes with unsuspected retinoblastoma. Ophthalmology 2000;107(12):2250–5. [31] Francis JH, Marr BP, Schaiquevich P, et al. Properties and clinical utility of topotecan fluorescence: uses for retinoblastoma. Br J Ophthalmol 2015;99(10):1320–2. [32] Francis JH, Marr BP, Brodie SE, et al. Intravitreal melphalan as salvage therapy for refractory retinal and subretinal retinoblastoma. Retin Cases Brief Rep 2015;1–4. [33] Che´vez-Barrios P, Chintagumpala M, Mieler W, et al. Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir. J Clin Oncol 2005;23(31):7927–35.