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Current treatment of optic nerve gliomas

Farazdaghi, Marybeth K.a,b; Katowitz, William R.a,b; Avery, Robert A.a,b,c

Current Opinion in Ophthalmology: September 2019 - Volume 30 - Issue 5 - p 356–363
doi: 10.1097/ICU.0000000000000587

Purpose of review Optic pathway gliomas are low-grade neoplasms that affect the precortical visual pathway of children and adolescents. They can affect the optic nerve, optic chiasm, optic tracts and radiations and can either be sporadic or associated with neurofibromatosis type one. Gliomas isolated to the optic nerve (ONG) represent a subgroup of optic pathway gliomas, and their treatment remains controversial. New developments in ONG treatment have emerged in recent years, and it is necessary for clinicians to have a current understanding of available therapies.

Recent findings The current review of the literature covers the background of and recent developments in ONG treatment, with a focus on standard chemotherapy, new molecularly targeted therapies, radiation therapy and surgical resection and debulking.

Summary Although standard chemotherapy remains the mainstay of ONG treatment, newer molecularly targeted therapies such as mitogen-activated protein kinase kinase inhibitors and bevacizumab represent a promising new treatment modality, and clinical studies are ongoing.

aDivision of Ophthalmology, The Children's Hospital of Philadelphia

bDepartment of Ophthalmology

cDepartment of Neurology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence to Robert A. Avery, DO, MSCE, Division of Ophthalmology, The Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104, USA. Tel: +1 215 590 2791; fax: +1 267 426 5015; e-mail:

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Optic pathway gliomas (OPG) are low-grade neoplasms that affect the precortical visual pathway and are most common in children and adolescents, representing 2–5% of childhood central nervous system tumors [1,2▪,3▪,4,5]. They are an important diagnostic consideration in any young child presenting with vision loss. OPGs can either occur sporadically, or in association with the tumor predisposition syndrome neurofibromatosis type 1 (NF1) [1,2▪,3▪]. Of children with NF1, approximately 20% develop OPG [6–9]. OPGs can involve any part of the precortical visual pathway, including the optic nerve, chiasm, tracts, radiations or the hypothalamus. We will focus our discussion on optic nerve gliomas (ONG) in children, which comprise approximately 25% of OPGs [10–12]. Although OPGs can rarely occur in adults, their management is much different and beyond the scope of this review.

The diagnosis of ONG can usually be made on the basis of neuroimaging and a comprehensive clinical exam. Sporadic ONGs only involve one optic nerve while those associated with NF1 can be unilateral or bilateral (Fig. 1). Biopsy is often unnecessary and carries a risk of vision loss [13▪]. When tissue is obtained, the most common histology is WHO grade I juvenile pilocytic astrocytoma, though pilomyxoid astrocytomas and grade II diffuse fibrillary astrocytomas have also been reported [14–16].



Due to their unpredictable behavior, OPG and, more specifically, ONG management is challenging for a number of reasons. ONG growth patterns are variable: some remain stable for years and never grow, while others demonstrate either rapid or slow growth patterns over many years. However, ONG growth by itself may not be an indication for treatment depending on the patient's current vision. Treatment is reserved for those patients with progressive vision loss or those with current vision loss and a high likelihood of experiencing further vision loss [1,2▪,3▪,17▪]. ‘Progression’ has proven difficult to define and there are differing opinions on the indications for treatment. The most frequent indications include loss of visual acuity and progression on neuroimaging [18], with clinically significant visual acuity loss considered to be 0.2 logMAR or more [19–21]. Visual field loss is also considered ‘progression,’ but due to the young of age of many of the OPG patients, formal perimetry may not always be feasible [1,17▪,19,22,23].

Many children diagnosed with ONG experience some degree of vision loss, resulting in a decreased quality of life [24]. It is well established that sporadic ONGs confer a much higher risk of vision loss compared with those secondary to NF1 [25–27]. In large studies of children with NF1 ONGs, visual outcomes following treatment tend to be better than those tumors involving the optic chiasm and or tracts [9,18,28,29].

Outcomes following standard treatments have been mixed and difficult to interpret given the paucity of standardized visual outcome measures and clinically meaningful definitions of treatment response/failure incorporated into most case series and clinical trials. These challenges and recommendations for metrics to be included in future trials have been discussed in detail elsewhere [3▪,17▪,18–20]. In this current review, we aim to evaluate the standard and emerging therapies for ONGs, with a summary of the roles of chemotherapy, molecularly targeted therapies, radiotherapy and resection and debulking.

Box 1

Box 1

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Standard chemotherapy

In patients with progressive disease, chemotherapy is the first-line treatment. As previously mentioned, criteria for disease progression remain controversial, but most agree that substantial tumor progression on MRI and/or worsening of visual acuity are acceptable indications for treatment with chemotherapy [18].

Once disease progression has been identified, treatment with the combination of vincristine and carboplatin has been the most common first-line treatment for ONGs. For patients with NF1 who undergo treatment with vincristine/carboplatin, the 3-year progression-free survival (PFS) rate is 77% [30] and the 5-year PFS is 69%, although these cohorts include gliomas beyond the optic nerve [31]. The regimen is generally well tolerated, although up to 40% of patients can experience hypersensitivity reactions to carboplatin [32,33]. Fortunately, secondary malignancies and treatment-related mortality were not observed in a large patient cohort [31].

Another regimen consisting of thioguanine, procarbazine, lomustine (CCNU) and vincristine (TPCV) showed a nonsignificant trend toward improved event-free survival when compared with carboplatin/vincristine in NF1 patients [31]. However, patients with NF1 are predisposed to leukemia [34–37] and there is an associated risk of secondary leukemia with both CCNU and procarbazine [38–40]. Thus, TPCV may be useful for those patients with sporadic ONG, but should be avoided in NF1.

The combination of cisplatin and etoposide has also been evaluated in the treatment of OPGs in patients with and without NF1 [41,42], with a 3-year PFS of up to 78% [41]. However, this regimen should be used cautiously, if ever, given the risk of secondary leukemia with etoposide [43] and ototoxicity with cisplatin [44]. In more recent years, monotherapies with temozolamide [45], vinblastine [46,47] and vinorelbine [48] have also been used for progressive or refractory disease with positive results and low toxicity, although temozolamide should also be avoided in NF1.

On the contrary, visual acuity improvement following chemotherapy is often modest at best. Most reported visual acuity outcomes reflect treatment with vincristine/carboplatin [18]. A large prospective study recently compared postchemotherapy visual acuity outcomes in OPG patients with and without NF1 [49▪▪]. There was no difference between groups, with 24% improving, 35% remaining stable and 41% worsening in the NF1 group and 18% improving, 43% remaining stable and 39% worsening in the sporadic group [49▪▪]. This result was consistent with prior studies [18]. Patients with gliomas isolated to the optic nerve seem to have better long-term visual outcomes than those with postchiasmatic disease [28,49▪▪], and some data suggest that ONGs are more responsive to chemotherapy than gliomas elsewhere in the optic pathway [50]. It should be noted that there has been poor correlation between radiographic results and visual acuity results in numerous studies [18,51–53].

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Molecularly targeted therapies: mitogen-activated protein kinase pathway inhibitors

Dysfunctional regulation of cell growth has been implicated in ONG, both sporadic and NF1-associated [54▪▪]. Knowledge of the mechanisms of tumorigenesis in low-grade gliomas continues to evolve, but is more established in NF1 [15,55–59]. The NF1 gene codes for the neurofibromin protein, which serves to regulate cell growth and proliferation through interactions with other downstream regulatory proteins [60]. These include Ras, which promotes cell division [60], B-Raf proto-oncogene, serine/threonine kinase (BRAF), which is an oncogene responsible for upregulating the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) signaling pathway [61–63] and mammalian target of rapamycin (mTOR), which is a serine/threonine protein kinase involved in many aspects of cellular division and growth [64,65]. Because neurofibromin functions as a tumor suppressor, NF1 dysfunction cases unregulated Ras and mTOR activity, leading to a promitotic state [1,66]. BRAF mutations have not been noted in NF1-associated pilocytic astrocytomas [59], but have been identified in many sporadic pilocytic astrocytomas [59,61,63].

MEK inhibitors such as selumetinib, refametinib, trametinib and cobimetinib have recently been employed in the treatment of progressive and recurrent low grade gliomas in children, with a 2-year PFS of up to 69% [67▪▪]. These agents target a downstream mediator in the Ras signaling pathway, preventing constitutive MAPK activation [68]. Their efficacy is likely greatest in those patients with BRAF mutations [67▪▪]. Notably, selumetinib has been associated adverse ocular effects in both adults and children. In early studies, adults treated with MEK inhibitors for advanced cancers that had failed prior treatment, cases of optic neuropathy, retinal vein occlusion, uveitis, neurosensory retinal detachment and MEK inhibitor-associated retinopathy have been reported [69–73]. In the pediatric population, there have been case reports of separation of the outer retinal layers as demonstrated on optical coherence tomography following selumetinib therapy; however, toxicity is much less common and is reversible for children, as compared with adults [74]. Molecularly targeted combination therapies are being investigated, but MEK inhibitors currently represent a viable option for salvage treatment in both sporadic and NF1-associated ONG [54▪▪,75].

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Molecularly targeted therapies: bevacizumab

OPGs are often highly vascular, and increased microvascular density has been associated with worse PFS [76]. Vascular endothelial growth factor (VEGF) induces neovascularization and is abnormally expressed in glial neoplasms [77,78]. Bevacizumab is an anti-VEGF monoclonal antibody [79] which has been successfully used as an antiangiogenic agent in multiple childhood malignancies [80–84]. By inhibiting VEGF, tumor growth and vascular permeability are reduced. Recently, bevacizumab has emerged as a promising treatment for OPGs, including those isolated to the optic nerve. Good responses have been achieved using bevacizumab as monotherapy and in combination with irinotecan or other traditional agents [85,86▪,87–89,90▪,91,92].

Bevacizumab-based therapy has achieved objective responses and rapid improvement in visual symptoms in up to 86% of refractory cases [93]. Combination therapy with bevacizumab and irinotecan achieved a 2-year PFS of 47.8% in patients with recurrent low-grade gliomas [87]. However, in the work of Hwang et al.[93] bevacizumab monotherapy given in a less dose-intensive schedule did not appear to decrease the efficacy of treatment and reduced toxicity when compared with combination therapy, suggesting that monotherapy is a viable option. In a series of four patients with OPGs (two with NF1, two sporadic) treated with bevacizumab monotherapy after initial treatment failure, moderate-to-significant visual improvement was achieved in all patients with decreased visual acuity [85]. Although disease may recur, there is evidence that retreatment with bevacizumab can achieve good responses [90▪,92].

Bevacizumab is not without side effects, most common being hypertension, fatigue, joint pain, bleeding events and proteinuria [85,87,90▪,91,93]. However, these are typically reversible after treatment is stopped. Given the good visual outcomes with bevacizumab-based therapy, it serves as an option for patients with refractory disease. Further studies are needed to elucidate whether earlier initiation of bevacizumab would lead to improvement in clinical outcomes.

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Radiation therapy

Although radiation therapy is an effective treatment for OPG, it is uncommonly used in current clinical practice given the burden of adverse effects on visual, neurocognitive and hypothalamic function. In the past, treatment with external beam radiation achieved up to 90% 10-year PFS [94–98]. However, this came at the expense of long-term endocrine abnormalities [96,97,99], cerebrovascular disease [100–102], poor visual outcomes [94–97], secondary malignancies [102–104] and neurocognitive deficits, particularly in young patients with developing brains [16,95,105]. Because patients with NF1 have a greater risk of neoplasia and cerebrovascular disease at baseline, these adverse outcomes are of particular concern in the NF1 population [100,101,104,106]. Regardless of NF1 status, radiation therapy has become a therapy of last resort and is typically reserved for older patients (i.e. teenagers) and those with no remaining chemotherapeutic options.

Newer methods of radiation therapy have been pursued to minimize the radiation dose to surrounding structures [107]. These methods include conformal treatment [108], fractionated stereotactic radiation therapy [109–111], proton beam radiation therapy [112,113], and stereotactic radiosurgery (Gamma Knife) [114,115]. Although positive results have been reported, long-term outcomes and adverse events are pending. These therapies continue to be used with caution, often for older children and teens with refractory disease.

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Surgical management: resection and debulking

Although surgery can be the primary treatment for pediatric low-grade astrocytomas in other locations [116], resection of gliomas isolated to the optic nerve is controversial and rarely indicated. In the past, radical resection of ONGs with the goal of complete tumor removal achieved prolonged disease stability [14,117,118]. There is some concern that sporadic gliomas isolated to the optic nerve can extend retrograde to the chiasm and cause vision loss [25,119–122]. Advocates for resection suggest that, with intracranial or intracanalicular involvement, resection of the entire length of the optic nerve should be performed to prevent spread, requiring a transcranial approach [10,117–119,123–125]. Spicer et al.[120] recently reported that tumor margins predicted by preoperative MRI may be inaccurate, with histopathologic evidence of neoplastic cells at posterior margins despite adequate resection. The authors argue that ONGs have been known to aggressively progress, and that surgical intervention should be considered earlier than would be suggested by MRI appearance [120].

It has been our experience, and the experience of other institutions, that ONGs identified with modern MRI do not typically progress to the chiasm and/or damage the crossing fibers from the contralateral eye [2▪,126]. Combined intracranial and intraorbital surgery confers a risk of visual [13▪], endocrinologic and cerebrovascular morbidity [116]. For this reason, many agree that surgery is indicated only in cases of painful or disfiguring proptosis, and exposure keratopathy in a severely visually impaired eye. It has been our experience that, in cases of ONG with a large orbital component resulting in significant axial proptosis with severe vision loss, discomfort due to exposure keratoconjunctivitis, and disfigurement, debulking surgery can result in improved cosmetic appearance with minimal risk of progression from residual tumor (Figs. 2 and 3).





ONG debulking surgery can thus be limited to the orbital component of the glioma, leaving a minimal portion of the tumor in the most posterior apex (if necessary) to minimize risk of postoperative cranial nerve injury (with the exception of the optic nerve itself). We have approached surgery via a standard lateral orbitotomy. This involves a modified eyelid crease incision to the lateral canthus, allowing for good exposure of the lateral orbital rim. The malar surface of the zygoma and orbital rim is incised superiorly and inferiorly and reflected laterally (Fig. 3). This allows for adequate exposure of the orbit. The periosteum is incised and the lateral rectus is retracted, exposing the ONG within the orbit. The tumor is lysed from the posterior globe surface leaving a small (approximately 2 mm) stump of tumor attached to the posterior sclera. The ONG is carefully dissected posteriorly and the tumor is lysed at the orbital apex taking care to leave a small portion of the nerve (if present) at the annulus of Zinn, which is the common tendinous ring surrounding the optic nerve at its entrance at the apex of the orbit. Care is made to preserve dissection over the posterior lateral rectus to prevent an injury to the ciliary ganglion, which can injure the nerves innervating the cornea. In our experience to date in five cases of ONG debulking via a lateral orbitotomy approach alone, we have experienced no complications, with the exception of one case of postoperative esotropia, which resolved within 6 months. Despite the lysis of the ophthalmic artery within the ONG, there were no cases of ocular ischemia, due to the additional blood supply to the eye via the anterior ciliary arteries. All of our five patients to date experienced a significant reduction in relative proptosis, with resolution of pain and improvement in cosmesis (Fig. 2).

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The management of ONGs remains challenging and our understanding of their behavior continues to evolve. Treatment is unnecessary for those sporadic and NF1-related ONGs that have not caused vision loss. When children manifest a decline in visual acuity, visual field or significant radiologic progression, chemotherapy with vincristine/carboplatin remains first-line. Fortunately, newer molecularly-target therapies such as MEK inhibitors and bevacizumab show promise in refractory cases and may become more widely used as ongoing phase 2 and 3 trials are completed. Radical surgical resection and radiotherapy, though successful in the past, are associated with high morbidity and should be reserved as a last resort. Debulking surgery can be safe and effective in cases where mass effect causes pain and disfigurement and vision is already limited. As our knowledge and experience with molecularly targeted therapies improves, hopefully the long-term impact and visual morbidity will be reduced for these children.

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Financial support and sponsorship

The work was supported by the National Institutes grant (R01EY029687; R.A.A.).

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Conflicts of interest

R.A.A. receives support from Ozmosis Research Inc (Toronto, Canada; funding supplemented by Hoffman-LaRoche and The Hospital for Sick Children, Toronto, Canada) for his role as Lead Ophthalmology Investigator for the study “A phase II, open-labeled, multicenter, randomized controlled trial of vinblastine ± bevacizumab for the treatment of chemotherapy naive children with unresectable or progressive low grade glioma.”

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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The phase I clinical trial established the tolerability and activity of the MEK inhibitor selumetinib in children with OPGs. These results formed the basis for ongoing clinical trials of MEK inhibitor therapy for OPG.

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The retrospective study of a 15-patient cohort demonstrated the efficacy of single-agent bevacizumab in recurrent/refractory pediatric OPG.

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The retrospective analysis compares single-agent bevacizumab with bevacizumab in combination with traditional chemotherapy. This article highlights the ability of bevacizumab to achieve rapid tumor control and preservation of vision.

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molecularly targeted therapy; optic nerve glioma; optic pathway glioma treatment

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