Optic pathway gliomas in adolescence—time to challenge treatment choices?

Abstract

Background

Optimal management of optic pathway/hypothalamic glioma (OPHG) remains an ongoing challenge. Little is known about the natural history, management strategies, and outcomes in adolescents. Carboplatin-based chemotherapy is a useful modality in younger children, delaying radiation to their immature brains. National trials have focused on younger children and excluded adolescents from studies evaluating the role of chemotherapy.

Methods

This retrospective study describes clinical characteristics, treatment regimens, and outcomes in adolescents (aged ≥10 years) with OPHG (diagnosis during 1990–2006). Progression-free survival was compared with that in a cohort of younger children (aged <10 years).

Results

Thirty-three adolescents (19 females, 6 with neurofibromatosis type 1) with OPHG were identified within 2 Canadian pediatric oncology institutions. The majority presented with visual symptoms (82%). More than 55% (18 of 33) involved the posterior tract and/or hypothalamus (modified Dodge classification 3/4). Seventeen were initially observed; 8 remained progression free. Of the 25 of 33 adolescents who required active treatment, 9 (36%) needed second-line therapy. The progression-free survival for any first active treatment at age <10 years (52 of 102) or ≥10 years (25 of 33) was similar (46.9 vs 46.8 months; P = .60). In those who received chemotherapy as first-line treatment or after prior nonchemotherapy treatment failure, the progression-free survival trend was superior (62.9 vs 38.9 months) in those aged ≥10 years although not statistically significant (P = .16).

Conclusions

Chemotherapy is a valuable treatment modality for the achievement of disease control even in adolescents; their progression-free survival compares favorably with that in younger children. We propose that chemotherapy be considered as a first-line modality in adolescents, avoiding potential radiation-associated morbidities.

The optimal treatment of children with optic pathway/hypothalamic gliomas (OPHGs) continues to be an area of controversy in contemporary literature and presents an ongoing challenge to pediatric oncologists. This arises from a number of factors, including the site of involvement, the variable natural history, and the disease-modifying effect of neurofibromatosis type 1 (NF1). Presenting at <1 year of age, diencephalic features, non-NF1 status, and location along the posterior pathway have been typically associated with a more aggressive disease course.^1–5 Published literature on OPHG has focused on the natural history, management strategies, and outcomes predominantly in the younger child. Radiotherapy continues to be the mainstay of progressive OPHG management strategies. In recent years, chemotherapy has emerged as a therapeutic option for those <10 years of age aiming to avoid or at least postpone radiation to the immature brain.⁶ Unfortunately, the adolescent population (aged ≥10 years) has been largely ignored and excluded from participating in national cooperative chemotherapy trials (POG 9952 and SIOP-LGG 1996).^7,8 In fact, many institutions continue to consider irradiation as the treatment of choice for progressive OPHGs in patients >10 years of age. This study will describe the natural history of OPHG in adolescents, their clinical features, management regimens used, and the outcomes in this cohort. It will also evaluate response to chemotherapy in children aged greater and <10 years at the time of therapy.

Materials and Methods

In this retrospective study, we describe a cohort of adolescent patients who received a diagnosis of an OPHG or who had their first active therapy at >10 years of age from 1 January 1990 through 31 December 2006. The age cutoff of ≥10 years used to define adolescence is consistent with the World Health Organization (WHO) definition. A request was made for eligible patients (who received a diagnosis of OPHG at aged ≥10 years that was confirmed by radiological [MRI/CT] imaging and/or on histology) to all institutions that participate in the Canadian Paediatric Brain Tumour Consortium. Approval for this study was obtained from the participating Institutional Research Ethics Boards.

Information relating to clinical presentation, initial management strategies, and treatment outcomes was abstracted from clinical charts and pathology/radiological records available up to 1 July 2011. Subjects were censored at the time that they were last seen or lost to follow-up or were transferred to another pediatric or adult institution. Tumors were classified on the basis of location along the optic pathway according to the modified Dodge classification (MDC; type 1 = involvement of optic nerve(s) alone, type 2 = optic chiasm with or without optic nerve involvement, type 3 = involvement of anterior optic tracts, and type 4 = posterior optic tracts ± hypothalamic involvement).⁹ The initial management strategy at presentation was defined as observation only (watch and wait policy [W + W]) or active treatment (surgery [Sx], radiotherapy [RT], and chemotherapy [CT]; each strategy alone or in combination). Surgical resection was classified as a debulking surgery or a gross total resection (GTR; complete tumor resection with no residual tumor visible at time of surgery or on subsequent radiographic imaging), whereas a biopsy or drainage of a cyst was not considered to be a surgical resection for the purpose of this review.

Progression-free survival (PFS) was defined as the time in months from the start of the first or subsequent management strategy to the start of the next treatment intervention or the last follow-up date. This definition was adopted because exact determination of a progression date is hard to define, given that progression of OPHGs encompasses new clinical symptoms and/or radiological changes. For adolescents who had a first active treatment (chemotherapy/radiation and/or surgery), further information pertaining to long-term clinical and quality of life outcomes (endocrine, second malignancy, school, and motor/behaviour/activities of daily living) was extracted from available medical records and from personal communication with their primary physicians.

To compare biological characteristics and management strategies between those aged greater or <10 years of age, we used all remaining patients with an OPHG diagnosis from the neuro-oncology and pathological database of the Hospital for Sick Children. To evaluate response to chemotherapy in those greater and <10 years of age, 2 comparison cohorts were constructed at the time of first chemotherapy exposure. Active therapy PFS was evaluated using Kaplan–Meier curves, and the log-rank test was used for statistical comparison of survival rates at a significance level of P < .05.

Results

A total of 33 adolescents (19 females; 58%) aged ≥10 years of age at diagnosis (n = 29) or time of first active treatment (n = 4) with an OPHG were identified at 2 Canadian pediatric oncology institutions during the study enrollment period (1 January 1990 to 31 December 2006). At last follow-up (1 July 2011), patients had been followed up for a median of 5.9 years (range, 0.8–14.7 years). Baseline clinical characteristics are outlined in Table 1. Six patients (18%) had NF1, based on clinical features and/or genetic testing. The mean age for the adolescent cohort at presentation was 11.7 years (range, 1.9–16.8 years), and there was no significant difference in mean ages between children with or without NF1 (P = .59). Of the 7 adolescents who were asymptomatic at the time of diagnosis; 3 patients newly received a diagnosis of NF1 and underwent MRI screening, 2 had abnormalities (optic pallor/atrophy) noted on routine ophthalmological examinations, and the remaining 2 had imaging performed for another reason (road traffic accident/sinus x-ray). Among the 26 adolescents who were symptomatic at presentation, visual defects (decreased acuity, diplopia, and proptosis) were the predominant presenting symptom (27 [82%] of 33). Information pertaining to their initial visual acuity assessment was available for 28 adolescents; normal (n = 17), moderate loss (2 unilateral and 1 bilateral), severe/profound loss (n = 2), and NLP (n = 2).

Table 1.

Presentation and diagnostic characteristics of patients with optic pathway gliomas by age at diagnosis

Variable	Total N (%)	Age First Active Treatment		P Value
		<10 y	≥10 y
		N (%)	N (%)
Total	135 (100.00)	102 (100.0)	33 (100.0)
Mean age at diagnosis (SD)	5.9 (4.2)	4.0 (2.4)	11.7 (2.9)
Gender
Female	69 (51.11)	50 (49.0)	19 (57.6)	.39
Male	66 (48.89)	52 (51.0)	14 (42.4)	.39
NF1 status
Yes	79 (58.52)	73 (71.6)	6 (18.2)	<.01
Presentation
NF1 screening/incidental	66 (48.89)	59 (57.8)	7 (21.2)	<.01
Symptomatic	61 (45.19)	36 (35.3)	25 (75.8)	<.01
Unknown	8 (5.93)	7 (6.9)	1 (3.0)	.42
Dodge grade
1	47 (34.81)	40 (39.2)	7 (21.2)	.06
2	46 (34.07)	38 (37.3)	8 (24.2)	.17
3 & 4	42 (31.11)	24 (23.5)	18 (54.5)	<.01

These visual findings occurred either in isolation or in conjunction with their neurological symptoms (headaches, behavioral changes, and cranial nerve [CN] VII palsy in one and an evolving left hemiparesis in another patient). On imaging, 7 had evidence of ventricular dilatation. More than half of the patients (n = 18) had extension into the optic tracts and/or infiltration into the hypothalamus (MDC 3/4). Of the 15 patients with hypothalamic involvement, one had evidence of central nervous system dissemination. Histological diagnosis obtained by confirmatory biopsy (n = 11) or by subsequent surgical resection was available for review in 25 (76%) of 33 and was consistent with a pilocytic astrocytoma (n = 13) or a low-grade glioma (n = 12).

The initial management strategy at presentation and subsequent treatment interventions used if progression occurred (radiological evidence or new clinical symptoms) in these 33 adolescents are outlined in Fig. 1 and Table 2. In 17 adolescents (10 females and 6 with NF1), the initial management strategy was to observe (W + W) for the development or progression of symptoms. Of these, 8 (4 with NF1) had stable disease and required no medical intervention; the 9 adolescents who experienced progression were treated with chemotherapy (n = 4), radiotherapy (n = 2), surgery (n = 2), and surgery/chemotherapy (n = 1) as their first active therapy. Sixteen adolescents (all aged >10 years of age at presentation) required a therapeutic intervention at diagnosis; of these, 7 (44%) underwent debulking surgery/GTR, 6 (38%) received chemotherapy, and 3 (18%) were treated with radiotherapy and/or surgical resection.

Fig. 1.

Management history of patients who received treatment for optic pathway glioma in adolescence.

Table 2.

Progression free survival (PFS) - from first active treatment to progression or end of follow-up by age at time of first active treatment

Variable					NF1 Status
	Total				No				Yes
			PFS in Months				PFS in Months				PFS in Months
	N	%	Mean (SD)	P Valuea	N	%	Mean (SD)	P Valuea	N	%	Mean (SD)	P Valuea
Age <10 yb	102	75.6	82.82 (58.58)		29	28.4	48.86 (45.92)		73	71.6	96.03 (57.88)
Presentation
NF1 screening/incidental	59	57.8		<.01	1	3.4		.27	58	79.5		.46
Symptomatic	36	35.3		<.01	23	79.3		.57	13	17.8		.35
Unknown	7	6.9		.42	5	17.2		.10	2	2.7		.68
Initial biopsy performed	15	14.7		.02	9	31.0		.45	6	8.2		.47
Watch and wait onlyc	50	49.0	120.18 (43.44)	.01	2	6.9	86.00 (–)	.34	48	65.8	120.90 (43.60)	.96
First active treatment	52				27				25
Surgical resection only	11	10.8	60.00 (43.82)	.02	6	20.7	68.17 (46.72)	.44	5	6.8	50.20 (43.04)	.38
Surgical resection and radiotherapy	1	1.0	–	.09	0	0.0	–	.14	1	1.4	–	.77
Surgical resection and chemotherapy	8	7.8	66.13 (80.74)	.34	6	20.7	52.17 (68.24)	.01	2	2.7	108.00 (132.94)	.09
Radiotherapy only	0	0.0	–	<.01	0	0.0	–	.07	0	0.0	–	–
Chemotherapy only	32	31.4	37.63 (37.07)	.91	15	51.7	37.33 (34.90)	.27	17	23.3	37.88 (39.95)	.18
Age ≥10 y	33	24.4	49.06 (39.52)		27	93.1	44.89 (40.01)		8.2		67.83 (33.97)
Presentation
NF1 screening/incidental	7	21.2			3	11.1			4	66.7
Symptomatic	25	75.8			23	85.2			2	33.3
Unknown	1	3.0			1	3.7			0	0.0
Initial biopsy performed	11	33.3			11	40.7			0	0.0
Watch and wait onlyc	8	24.2	56.13 (25.33)		4	14.8	37.25 (19.92)		4	66.7	75.00 (12.25)
First active treatment	25				23				2
Surgical resection only	9	27.3	37.00 (35.68)		8	29.6	41.00 (35.92)		1	16.7	5.00 (–)
Surgical resection and radiotherapy	2	6.1	33.00 (35.36)		2	7.4	33.00 (35.36)		0	0.0	–
Surgical resection and chemotherapy	1	3.0	102.00 (–)		0	0.0	–		1	16.7	102.00 (–)
Radiotherapy only	3	9.1	27.67 (23.71)		3	11.1	27.67 (23.71)		0	0.0	–
Chemotherapy only	10	30.3	58.60 (53.34)		10	37.0	58.60 (53.34)		0	0.0	–

^aTests the difference in proportion between age groups.

^bThere are two subjects where follow-up time is unavailable that are therefore not included in any of the mean event free survival calculations for this age group.

^cFor watch and wait only patients, age was based on time of diagnosis.

In addition to the 4 adolescents (patients 9, 10, 12, and 13) who underwent a GTR of the optic nerve after complete visual loss, a total of 21 adolescents (patients 1–8, 11, 14–21, and 30–33) received a first-line therapeutic intervention either at presentation or after development of symptoms. Of those 21 adolescents, 9 (43%) required a second line of therapy (patients 1, 8, 11, 15, 16, 18, 21, 30, and 32). Of the 5 adolescents who had first-line radiotherapy and/or surgery (patients 7, 15, 16, 19, and 21), 3 experienced progression after a mean of 30 months (range, 8–58 months; patients 15, 16, and 21). Fifteen adolescents received chemotherapy, 11 as a first-line agent (73%; patients 1–6, 17, and 30–33) and 4 after prior interventions (1 surgery and 3 surgery and radiation ) had failed (patients 8, 11, 15, and 16). Twelve (80%) of these 15 adolescents were progression free at a mean of 52.9 months (range, 9–149 months); one had radiological features suggestive of progression while receiving chemotherapy and, therefore, proceeded to radiation after the first 6 months (patient 1). Radiological and visual responses (where available) of those who had first active treatment with chemotherapy or radiation are presented in Table 3.

Table 3.

Radiological/visual response and long-term outcomes of patients who received radiation or chemotherapy as first active treatment

PT ID	Radiological Response	PFS (mo)	Initial Visual Acuitya	Initial Visual Field	Visual Acuity Response	Visual Field Response	Long Term Outcomes
							Endocrine Deficit	Second Malignancy	School	Motor Behavior/ADL
Patients who received radiation as first active treatment
7	SD	53	Normal	Bilat lower temporal fields	Stable	Improved	GH deficiency	None	Main stream	No known issues
15	PR	8	NLP Rt	Rt temporal & central scotoma	Improved	ND	Amenorrhea	None	Needs help reading	Lt hemiparesis
				Lt temporal & central scotoma			Obesity
16	PD	58	Severe Lt	ND	ND (normal last exam)	Normal last exam	Hypothyroidism	Cutaneous T-Cell Lymphoma	Main stream	No known issues
							Obesity		Short-term MD
19	SD	82	Normal	Lt nasal & inferior fields	Improved	Improved	None	None	Main stream	Premorbid ADHD
21	SD	24	Severe Lt	Rt homonymous hemianopia	ND	ND	None	None	Profound neurological compromise due to peri-operative complications
Patients who received chemotherapy as first active treatment
1	PD	6	ND	Lt temporal field	Decreased	Stable	None	None	Main stream - VA	No known issues
2	PR	44	Normal	Lt homonymous hemianopia	Stable	Improved	None	None	Main stream	No known issues
3	SD	65	ND	Normal	Stable	Decreased	None	None	Main stream	No known issues
4	SD	70	Normal	Bitemporal hemianopia	Stable	Stable	None	None	Main stream	No known issues
5	SD	73	Normal	Lt homonymous hemianopia	Stable	ND	None	None	University	Seizure Disorder
6	SD	77	ND	Rt homonymous hemianopia	Improved	Stable	PCOS‡	None	Main stream	No known issues
17	PR	70	ND	Rt nasal & Lt temporal field	Decreased	Improved	None	None	Main stream	No known issues
30	SD	30	Normal	Lt homonymous hemianopia	Stable	Decreased	None	None	Main stream	Lt hemiparesis
31	SD	51	Normal	Normal	Improved	Stable	Obesity	None	Main stream	Rt hemiparesis
32b	PR	7	Normal	Normal	Stable	Stable	None	None	Main stream	No known issues
33	SD	23	Normal	Rt temporal field	Stable	Improved	None	None	Applied stream – LD	No known issues

Abbreviations: ADL, activity of daily living; Bilat, bilateral; GH, growth hormone; LD, learning difficulty; Lt, left; MD, memory deficit; ND, not documented; NLP, no light perception; PCOS, polycystic ovarian syndrome; PD, progressive disease; PFS, progression-free survival (in months); PR, partial response; Rt, right; SD, stable sisease; VA, visual aids.

^aAs per ICD-9 classification – normal (normal to near-normal visual acuity); Severe (severe/profound visual loss).

^bHas NF1.

At the time of this review, all 33 adolescents are alive; 14 (42%) are still attending pediatric services, 15 (45%) have been transferred to adult services, and 4 (12%) have been transferred to another pediatric institution (n = 1) or were lost to follow-up. Available long-term follow-up data on those who received chemotherapy (n = 11) or radiation (n = 5) as first active therapy (with or without surgery) are presented in Table 3. Of note, those who received chemotherapy as first active therapy had virtually no endocrinopathies at their last follow-up. During the follow-up period, one of these adolescents developed a cutaneous T cell lymphoma outside her radiation field, which was treated with topical steroids. Three (11%) of these 16 adolescents have a documented neurological morbidity: one as part of his presenting symptoms (patient 30), one as a result of a peri-operative complication (patient 21), and one as a result of a spontaneous intra-tumor hemorrhage (patient 5) from which he completely recovered. At last follow-up, the majority of these adolescents were attending mainstream schooling; 3 required educational support for visual or cognitive needs.

One hundred two patients who received a diagnosis of an OPHG and/or who had first-line active treatment at <10 years of age were identified in our institutional neuro-oncology and pathology database from 1 January 1990 through 31 December 2006. Baseline characteristics of this cohort are outlined in Table 1. Almost 50% (50 of 102) of this younger OPHG cohort were observed after the initial diagnosis and did not receive any active treatment during the study period. To evaluate response to active medical intervention, we compared the adolescent cohort (n = 25) with those in the younger cohort (n = 52) who had received a first-line therapy (chemotherapy/radiation with or without surgery) either at time of diagnosis or after a period of observation. Baseline characteristics of these 2 cohorts are outlined in Table 1.

Among the adolescent cohort who received first-line therapy (n = 25), the mean age at diagnosis was 11.3 years (range, 1.9–14.5 years); 2 (8.0%) had NF1, and 16 (64.0%) were MDC 3/4. The mean follow-up time was 6.2 years (range, 0.8–17.3 years), and 9 patients (36.0%) experienced progression after first active treatment. Twelve patients (48.0%) underwent a primary surgical resection, of whom 6 required a second active treatment agent. The mean time to treatment with chemotherapy as a first-line agent (11 patients) was 62.5 months (range, 3–184 months) from time of diagnosis.

Among the younger cohort (n = 52), who all received first active therapy at <10 years of age, the mean age at diagnosis was 3.7 years (range, 0.4–9.6 years); 25 (48.1%) had NF1, and 20 (38.5%) were MDC 3/4. The mean follow-up time was 9.4 years (range, 0–18.4 years), and 26 patients (50%) experienced progression after first active treatment. The mean time to treatment with chemotherapy as a first-line agent from time of diagnosis was 5.1 months (range, 0–67 months) in this younger cohort. Among only patients without NF1in the younger cohort, the mean time to treatment with chemotherapy was 2.3 months (range, 0–25 months). PFS among those who received any first active therapy (not including gross total resection) who were aged <10 years and >10 years was not significantly different (P = .60) (Fig. 2). After restricting the analysis to those who received chemotherapy either as first-line therapy or after prior nonchemotherapy treatment failure, the PFS was 62.9 months among those aged ≥10 years and, therefore, superior, compared with those <10 years of age (38.9 months), although not statistically significant (P = .16 ) (Fig. 3).

Fig. 2.

PFS in patients aged < or ≥10 years at time of any first active therapy (RT/CT).

Fig. 3.

PFS in patients aged < or ≥10 years at time of first chemotherapy.

Discussion

OPHGs are low-grade gliomas that occur predominantly during the first 2 decades of life. The disease-modifying effect of NF1 on the OPHG is well documented.¹⁰ Recent evidence suggests that older children and young adults with NF1 are still at risk to develop a new lesion or experience progression of a previously quiescent tumor.¹¹

Current literature has predominantly focused on the natural history, management strategies, and outcomes of OPHG in the younger child. Adolescents with OPHG have been largely ignored; published reports including them have not identified them as a distinct patient population and have primarily focused on those with NF1-associated OPHG.^11–14 No published article to our knowledge has reported on the natural history of OPHG in teenagers or compared management strategies and outcomes in those aged less than and greater than 10 years of age.

We have, to our knowledge, assembled the largest cohort of adolescents with OPHG to date. They received diagnoses over a 17-year period, during which management strategies changed from reliance on surgery and/or radiation to the use of chemotherapy as first-line therapy for disease control. The decision to proceed to an active treatment intervention was based on the severity or rapid progression of symptoms (particularly visual symptoms), the child's age, NF1 status, tumor location, and size. All patients were clinically monitored for progression, in conjunction with regular MRI imaging and ophthalmological examinations.

The 5 patients with NF1 who presented during the adolescent period (aged >10 years) most likely represent late diagnoses of missed or minor clinical stigmata and slowly progressive, previously unrecognized tumor development. The patient with NF1 in our study with the greatest tumor burden (MDC 4) showed progression of disease (on visual examination and radiological imaging) after an observational period of 5 months. At that time, the patient proceeded to initial debulking surgery only and remained stable. After almost 4 years, the patient showed further radiological progression and was, at this point, treated with focal radiation; this management strategy was reflective of the therapeutic approach at that time and would not be advocated currently.

The majority of these adolescents did not have NF1 (27 [81.8%] of 33), were symptomatic at diagnosis (26 [78%] of 33), and had significant disease burden (18 [54.5%] of 33 were MDC 3/4). This is very different from the clinical presentation of children who received a diagnosis at <10 years of age (n = 102) at our institution (71.6% had NF1 [P < .01], 35.3% were symptomatic [P < .01], and only 23.5% were MDC 3/4 [P = .01]). In comparing the non-NF1 patients alone, this trend persists (although nonsignificantly), with a higher proportion of adolescents being symptomatic at presentation (85.2% vs 79.3%; P = .57) and presenting with more significant disease burden (MDC 3/4; 59.3 vs 44.8; P = .28). Adolescents were more likely to have a biopsy to confirm the diagnosis (33.3% vs 14.7%; P = .02), which reflects the standard of care in the absence of clinical stigmata of NF1.

Over the study period, different chemotherapy regimens were used; most of the participants received carboplatin with or without vincristine.⁷ Other regimens included thioguanin, procarbacin, CCNU, and vincristine⁷ and vinblastine¹⁵ or carboplatin monotherapy. Only 2 (17%) of 12 adolescents treated with carboplatin and vincristine developed carboplatin allergies, which is markedly less than reported in previously published studies.^16,17 In these 2 cases, one was successfully desensitized and the regimen was changed to vinblastine monotherapy in the other.¹⁸ In addition to these 2 adolescents, 2 others required a carboplatin dose reduction because of hematological toxicity, and 2 developed vincristine neuropathies requiring dose adjustments.

Contemporary oncologists strive to minimize long-term sequelae of therapy, and in diseases such as OPHG, in which the overall survival rates suggest a normal life expectancy for the majority of patients, this is particularly important. In OPHG, when considering the risk of long-term sequelae, we must be cognizant of the influence of the tumor mass (local compression and/or infiltration into adjacent structures) and the higher vulnerability of patients with NF1 to the secondary effects of radiation, in particular Moya Moya syndrome.¹⁹ At this time, an optimal management regimen in patients with OPHG continues to be an area of controversy in published literature and presents an ongoing challenge to pediatric oncologists. The reason for this, as mentioned previously, relates to the complexity of the tumor behavior, its deep-seated location within important brain structures, and associated variable clinical symptoms. This therapeutic conundrum is further complicated by an inability to accurately predict those who will have a more aggressive disease course because of limited clinical, histological, or radiological prognostic markers.²⁰ There is hope that recently identified molecular markers may aid in the future decision process.^21,22

Most centers prefer to longitudinally observe patients with NF1 with OPHGs, and indications to treat include onset/worsening of visual disturbance, neurological defects, and endocrinopathies. Depending on clinical factors, local resources, and physician preference, current active management options include single/multi-modality therapy with surgery, chemotherapy, or radiotherapy. Complete surgical resection is possible and curative in MDC1 cases but is typically reserved for cases in which visual loss of the affected eye has occurred. However, surgical intervention for those patients whose tumors often involve midlines structures, such as thalamus, hypothalamus, and optic chiasm will be limited and most commonly relates to decompression. Historically, radiotherapy (45–60 Gy) has been the standard of care for OPHG with reported 10-year PFS rates of 69%–89%.^23,24 Associated long-term toxicities include endocrinopathies, vasculopathies (ie, Moya Moya), secondary malignancies (relative risk, 3.04), and neuro-cognitive challenges.^24–28 The Childhood Cancer Survivor Study reported a relative risk of 29 (95% confidence interval, 13.8–60.7) of late-occuring stroke for brain tumor survivors, with a significantly higher occurance in those treated with cranial radiation. The cumulative incidence for brain tumor survivors treated with cranial radiation was 6.9% (95% confidence interval, 4.47%–9.33%) at 25 years.^29,30 One may argue that with recent advances, including fractionated stereotactic radiotherapy, intensity modulated radiotherapy, and proton therapy, less long-term morbidites may be achievable;³¹ however, data on late effects are still in their early stages.

Several studies have shown that chemotherapy (particularly carboplatin-based regimens) is a useful modality, particularly in young children with low-grade gliomas, with reported 3-year PFS of 53%–78%³² and 5-year PFS of 45%–63%.^7,33,34 In this population, at the very least, it facilitates the postponement of radiotherapy until the child is older.^1,6,33,35 This delay in use of radiotherapy has been shown to have no negative impact on overall survival among these patients.²⁵ National cooperative group studies [Children's Oncology Group (COG), International Society of Paediatric Oncology (SIOP)] have implemented chemotherapy as a first-line treatment strategy for children <10 years of age to minimize radiation-associated sequelae to the immature brain (POG9952; SIOP-LGG-1996). With rare exceptions, most collaborative studies to date have not evaluated the therapeutic potential of chemotherapy in patients with OPHG >10 years of age, in fact these adolescent patients have been generally excluded from trial participation. A study from Health et al.³⁶ in 7 patients with intracranial low-grade gliomas who were aged >10 years (3 with an OPHG: 2 optic nerve and 1 optic tract) at the time of treatment suggests that chemotherapy has a role in the future treatment strategy in these patients (PFS was 71%). The present retrospective review supports the chemoresponsiveness of OPHG in adolescents with response rates comparable to those among young children and, thus, advocates that chemotherapy be considered as a first option in patients >10 years of age.

We acknowledge that limitations of this study include the small number of participants in the adolescent cohort and the relatively short follow-up times because of the transition of patients to adult centers. However, our study clearly shows that PFS after chemotherapy in this cohort of adolescents with OPHGs is at least comparable to that seen among those treated at a younger age. These findings, coupled with the unpredictable nature of these tumors, support our belief that patients with OPHG who are aged>10 years at diagnosis are a distinct population and that they deserve consideration for a chemotherapeutic approach, thereby allowing a delay in the use of a radiation strategy, particularly in view of its associated sequelae. The need for a multidisciplinary approach to care, with the involvement of pediatric neurosurgery, ophthalmology, and neuro-oncology services continues beyond early childhood and should be tailored to minimize treatment morbidities in a chronic and not only life-threatening disease. Chemotherapy proved to be a viable first-line treatment option in the adolescent with a progressive OPHG. We propose to include adolescents into cooperative trials to better evaluate short- and long-term outcomes in patients all ages with OPHG.

Conclusion

The natural history of OPGs in adolescents and the management strategies used are different from those seen in younger childhood. In the teenage population, radiotherapy remains the first-line standard of care in many centers. This retrospective review questions the appropriateness of upfront use of radiation therapy because of associated long-term sequelae and evident chemotherapy responsiveness even in older children. This review also supports chemotherapy as a valuable treatment modality and advocates that it should be considered as a first-line treatment to minimize treatment-related morbidities in adolescents affected by OPHG but with a normal average life expectancy.

Funding

Dr. Lee Chong received salary support from the Paediatric Oncology Group of Ontario.

Conflict of interest statement. None declared.