Pediatric spinal cord gliomas—low grade but high risk for recurrence: should we treat them differently from intracranial low-grade gliomas?

See the article by Perwein et al., pp. 1148–1162.

Spinal cord low-grade gliomas (LGGs) in children are rare, but nevertheless, comprise a clinically and biologically heterogeneous spectrum of disease. Children and adolescents of all ages can be affected and may present with localized or disseminated disease.¹ Prior studies are confounded by retrospective design, inclusion of adult patients, and mixed tumor types (LGGs and high-grade gliomas) or localization (spinal and intracranial) and may reflect the bias inherent to tertiary referral centers with inclusion of higher proportion of recurrent/refractory patients.^1–3 Therefore, limited prospective data exclusive to spinal cord LGGs are available with respect to epidemiology, risk factors, molecular characteristics, treatment strategies, and functional outcomes.

In the current issue of Neuro-Oncology,⁴ Perwein et al provide a detailed analysis of natural history, management strategies, treatment response, prognostic factors, and clinical outcome for the largest cohort (n = 128) of pediatric spinal LGG patients reported to date. Patients enrolled and treated on two cooperative group trials HIT-LGG-1996 (n = 36)⁵ and SIOP-LGG-2004 (n = 56),⁶ as well as those enrolled on the LGG-Interim registry (n = 36) are included. Data on functional outcomes and long-term sequelae were available in most, and tissue for molecular characterization in a subset of patients. Very few patients were lost to follow-up and long-term data are provided (median follow-up of 8.8 years), which is critical given the chronic nature of LGG, thereby enabling meaningful analyses.

The data are leveraged to help prognosticate spinal cord LGGs using clinical and molecular characteristics and inform a rational treatment approach. In doing so, the study further validates some well-established concepts but also begins to address some unanswered questions. Spinal cord LGGs are associated with specific therapeutic challenges. While most patients will survive their disease, they are often left with a lifetime of devastating neurological and orthopedic sequelae, including kyphoscoliosis, motor disability, pain, and decreased quality of life.^1–3 The manuscript confirms that the vast majority of children will become long-term survivors (10-year overall survival [OS] 93 ± 2%). Despite this, many children are faced with tumor recurrence (10-year event-free survival [EFS] 38 ± 5%) and treatment-related morbidities. Uni- and multivariable Cox regression analyses revealed older age (>11 years), gross total resection, and localized disease to be favorable prognostic factors.

Surgery alone, consisting of single (n = 60) or multiple (n = 17) procedures in the absence of medical therapy, resulted in disease control (stable disease/complete remission) in the majority of patients (73 of 77 patients). Forty-seven patients received medical therapy as first-line management with a standard LGG chemotherapy regimen (n = 35) or radiation therapy (n = 12) A striking observation is the excellent disease control rate with first-line radiation therapy (5-year progression-free survival [PFS] of 92 ± 8%), whereas patients receiving first-line chemotherapy had 5-year PFS rates of 62 ± 11% (excluding patients with disseminated disease), similar to disease control rates in intracranial LGG.⁷ This observation raises important treatment considerations. Whereas concerns of long-term neurocognitive and endocrine sequelae from radiation therapy are of great importance when choosing adjuvant therapy for intracranial LGGs, these do not apply to patients with spinal cord tumors. The increasing use of proton irradiation may help limit exposure of unaffected tissues further and thereby reduce the long-term sequelae including risk for second malignant neoplasms. The excellent disease control rates after focal radiation therapy suggest that this treatment modality merits high priority when adjuvant therapy is required. Nonetheless, irradiation of the spine in young children may affect longitudinal growth, which was not assessed in the current study and should be factored into decision making.

One alarming aspect of the study was the report of malignant transformation (MT) in 6 patients (H3K27M and BRAFV600E negative, 4 with dissemination, 3 with previous irradiation), exceeding prior reported rates of 2-3%.⁸ These findings emphasize the importance of re-resection or biopsy in the event of tumor progression, when feasible.

Functional improvement or stability were achieved in the majority (86%) of patients, however, severe functional deficits persisted in approximately 20% of the cohort. Kyphoscoliosis was present in a quarter of patients at diagnosis, while an additional 30% developed spine deformities following treatment regardless of modality (surgery, chemo- or radiotherapy). Most of these patients, however, did not require surgical interventions.

Finally, the authors confirm that spinal cord pLGGs are, similar to their intracranial counterparts, by and large a disease of aberrant MAPK pathway activation,^9,10 with the majority of tested tumors harboring BRAF-KIAA1549 fusions (40%), and less commonly FGFR1-TACC1 fusions (12%) and BRAFV600E mutations (3%). No alterations in H3.3K27M (as seen in diffuse midline high-grade gliomas), TP53, FGFR1, or PTPN11 were identified, in keeping with previously published data.¹⁰ No relevant associations between molecular-pathologic findings and clinical outcomes were observed, and this analysis was limited due to the availability of tissue for molecular testing.

The authors’ observations provide clinicians with the tools to individualize the timing and selection of tumor-directed interventions for each patient with spinal cord LGG based on clinical characteristics, severity of clinical symptoms, and functional status at presentation. The low mortality but high morbidity rates in pediatric spinal cord LGG patients highlight the need to focus on functional outcomes rather than survival alone. Accordingly, future clinical trials should include systematic evaluation of both immediate and late toxicities, while incorporating functional outcomes (such as motor abilities), quality of life, and neuro-psychological assessments. Moreover, several important questions remain unresolved, including the role of molecularly targeted agents, such as BRAF and MEK inhibitors, in this population. It is hoped that future prospective studies will build on the observations made, and ultimately lead to further improvements in both tumor control and functional outcomes for children with spinal cord LGG.

Funding

None declared.

Conflict of interest statement. S.F.S. declares consulting agreements with AstraZeneca (personal fees received) and QED Therapeutics. M.A.K. declares consultant agreements with AstraZeneca, Bayer, CereXis, Recursion Pharmaceuticals, and QED Therapeutics (personal fees received).