# Radiation Oncology/Optic Pathway Glioma

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Optic Pathway Glioma

## Epidemiology

* Low grade astrocytic tumors
* Prevalence
** 2% of cerebral gliomas
** 5% of childhood brain tumors
** 90% in children <20 years, 75% in <10 year olds; 10% in adults
* Associated with neurofibromatosis
** 30% of OPG patients have NF1 stigmata
** Up to 25% of NF1 patients develop OPG (most common CNS tumor in NF1)
* Location
** Anterior (orbital, infracanalicular, prechiasmal) - common in prepubertal children
** Posterior (chiasm, hypothalamus, anterior 3rd ventricle) - common in adolescents

## Treatment

* Optimal management of optic pathway gliomas is controversial
** Patient age
** Tumor location
** Presence of NF1
* Children should probably be managed with observation and close follow-up, if possible
* Adults should be managed aggressively
* Non-surgical treatment algorithm as per PMID 16411210
** <3 years or 3-10 with unresectable lesion
*** Observe until radiographic or symptomatic progression
*** Packer regimen (carboplatin/vincristine); if no progression, observe; if progression, RT
** >10 years
*** Proton RT if available, else stereotactic/conformal RT; if no progression, observe; if progression, protocol

### Surgery

* No consensus regarding optimal timing
* Likely benefit:
** Obstructive hydrocephalus
** Single nerve involvement causing progressive disfiguring proptosis or blindness
* Possible benefit: delaying RT in young children
* Probable contra-indication:
** Diffuse chiasmal involvement/broadly infiltrative disease
** NF patients

### Chemotherapy

* No consensus; most are treated under Low Grade Glioma guidelines
* UCSF study demonstrated activity of nitrosurea-based chemo (TPDCV)
* George Washington study (Packer) demonstrated good outcomes with carboplatin/vincristine (now the most "standard" chemo)
* French trial showed good long-term control, while avoiding RT
* Children's Oncology Group trial CCG A9952 recently reported(essentially randomizing UCSF and GW protocols)
Published
* CCG A9952 PMID 22665535 -- "Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group." (Ater JL, J Clin Oncol. 2012 Jul 20;30(21):2641-7.)
** Prospective RCT. 274 patients < 10 years of age with progressive or residual LGG. Randomized to carboplatin and vincristine (CV) or thioguanine, procarbazine, lomustine, and vincristine (TPCV).
** 5-year outcomes: EFS 39% (CV) vs. 52% (TPCV) (stratified log-rank test P = .10; cure model analysis P = .007)
** Prognostic factors: younger age and tumor size greater than 3 cm2 (worse EFS and OS), thalamic tumors (worse OS)
** Conclusion: Differences in toxicity may influence treatment decisions.
* French Society of Pediatric Oncology, 2003 (1990-1998) PMID 14673044 -- "Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy--results of the first French prospective study for the French Society of Pediatric Oncology." (Laithier V, J Clin Oncol. 2003 Dec 15;21(24):4572-8.)
** Prospective. 85 children with progressive optic pathway tumors. Chemo: alternating procarbazine/carboplatin, etoposide/cisplatin, and vincristine/cyclophosphamide every 3 weeks. At relapse, 2nd line chemo before RT
** 5-year outcomes: PFS 34%, OS 89%. RT-free survival 61%
** Prognostic factors: age <1, NF1 associated with disease progression
** Conclusion: RT can be avoided with prolonged chemotherapy, without compromising OS or visual function
* Royal Marsden, 2003 (UK) PMID 12892235 -- "Tolerance of nitrosurea-based multiagent chemotherapy regime for low-grade pediatric gliomas." (Lancaster DL, J Neurooncol. 2003 Jul;63(3):289-94.)
** Prospective. 10 children with low-grade gliomas, initially treated with carboplatin/vincristine, second line with TPCV
** Conclusion: TPCV is appropriate as second line therapy
* George Washington, 1997 PMID 9126887 -- "Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas." (Packer RJ, J Neurosurg. 1997 May;86(5):747-54.)
** Prospective. 78 children with progressive low-grade glioma (12 brainstem gliomas). Concurrent carboplatin/vincristine. Median F/U 2.5 years
** 3-year PFS: 68%. No difference between NF1+ and NF1-. Objective response 56%
** Prognostic factors: only age (<3 yo 74% vs. >3 yo 39%, SS)
* UCSF, 1991 (1983-1989) PMID 1901597 -- "Management of chiasmal and hypothalamic gliomas of infancy and childhood with chemotherapy." (Petronio J, J Neurosurg. 1991 May;74(5):701-8.)
** Retrospective. 19 children with chiasmal/hypothalamic gliomas. 12 treated immediately for progressive symptoms, 7 deferred. Chemo: TPDCV
** Median time to progression: not reached at 20 months. No tumor-related deaths. Initial response/stabilization 15/18 patients
** Salvage: RT
** Conclusion: TPDCV allows RT to be deferred until progression of disease.

## Radiation

* Most favorable outcomes reported for 45-56 Gy, in 1.8 Gy/fx
* Suggestion that posterior location tumors have worse outcomes
* Proton RT is being explored
* Harvard, 2005 (1992-1998) PMID 15667955 -- "Stereotactic radiotherapy for localized low-grade gliomas in children: final results of a prospective trial." (Marcus K, Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):374-9.)
** Prospective. 50 patients with localized low-grade glioma. RT for progression on/after chemo or surgery. Median F/U 6.9 years
** RT: Removable head frame. 2-mm margin. Mean dose 52.2 Gy in 1.8 Gy/fx. Target delineation via CT/MRI fusion
** 5-year outcome: PFS 83%, OS 98%; 6 patients with in-field progression, no marginal failures
** Conclusion: stereotactic RT excellent local control, with limited margins
* Heidelberg, 2005 (Germany) (1990-2003) PMID 15936565 -- "Fractionated stereotactic radiotherapy of optic pathway gliomas: tolerance and long-term outcome." (Combs SE, Int J Radiat Oncol Biol Phys. 2005 Jul 1;62(3):814-9.)
** Retrospective. 15 patients. Median dose 52.2 Gy (45.2-57.6) in 1.8 Gy/fx. Median F/U 8 years
** 5-year outcome: PFS 72%, OS 90%. No second malignancies
** Conclusion: Good control, normal brain sparing. Longer f/u needed
* Institut Curie, 1991 (1970-1986) PMID 1907959 -- "Chiasmal gliomas: results of irradiation management in 57 patients and review of literature." (Bataini JP, Int J Radiat Oncol Biol Phys. 1991 Aug;21(3):615-23.)
** Retrospective. 57 patients, 37% chiasm, 63% extended to hypothalamus/posteriorly. RT 40-60 Gy. Mean F/U 7.5 years
** 5-year (and 10-year) OS: 84%; response: CR 15%, PR 46%, SD 22%
** Conclusion: RT effective in cases of rapidly developing visual, neurological, or endocrine symptoms
* Neurological Institute, Columbia University, 1956 PMID 13323290 -- "The value of radiation therapy in the management of glioma of the optic nerves and chiasm." (Taveras JM, Radiology. 1956 Apr;66(4):518-28.)
** Retrospective. 34 patients treated with RT
** Survival: 23/34 at time of publication
** Landmark study. Results deemed exceptional. Launched RT as a management strategy

## RT Complications

* Manchester/London, 2006 PMID 16735710 -- "Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy." (Sharif S, J Clin Oncol. 2006 Jun 1;24(16):2570-5.)
** Retrospective. 58/80 NF1 patients with OPG. 18/58 RT alone or in combination. Dose 25-50 Gy
** Second CNS tumor: RT 9/18 (50%) developed 12 second tumors in 308 person-years of F/U; No RT 8/40 (20%) developed 9 second tumors in 721 person-years of F/U. RR 3 (SS). Median time-to-diagnosis 12 years. Risk of MPNST was increased RR 5.3 (SS) over non-OPG NF1 controls
** Conclusion: Significantly increased 2nd CNS cancer risk in NF1 patients with OPG; RT should be used only if absolutely necessary
* Toronto, 1993 (1971-1990) PMID 8315466 -- "Moyamoya phenomenon after radiation for optic glioma." (Kestle JR, J Neurosurg. 1993 Jul;79(1):32-5.)
** Retrospective. 47 patients with OPG treated.
** Moyamoya phenomenon: 0/19 no RT; 5/28 with RT; 2/23 NF1- vs. 3/5 NF1+ (SS)
** Conclusion: High incidence of moyamoya in patients with NF1 and cranial RT
** Note: Moyamoya disease is a progressive chronic cerebrovascular disease seen mainly in Asia characterized by bilateral stenosis/occlusion of the arteries in the circle of Willis with an unknown etiology that here used to describe post-radiation changes to the vascular system

## Review

* 2006 PMID 16411210 -- "Optic pathway gliomas." (Jahraus CD, Pediatr Blood Cancer. 2006 May 1;46(5):586-96.)