Although most subjects with NF1-OPG had improvement or stabilization of vision after treatment with chemotherapy, VA worsened in 28% of subjects and 21% of eyes despite treatment. It is unknown whether some of the visual worsening during therapy reflected damage that had already occurred prior to treatment as opposed to continued tumor progression. In this regard, there are few studies in the literature specifically designed to assess the utility of chemotherapy for vision preservation. A recent meta-analysis identified only 8 “high-quality” publications in the literature that examined the visual outcome of OPG treated with chemotherapy.11
Only 1 of these studies was multi-institutional, and the largest included 57 subjects with visual outcomes. Of the 174 subjects in the meta-analysis, 14.4% had improvement, 47.1% stability, and 38.5% worsening of vision following chemotherapy. The applicability of the conclusions to clinical practice suffers from the limitations of the studies reviewed, including lack of a clear definition of visual response, lack of quantitative assessment of vision, or lack of within-subject evaluation. In addition, the wide range of time points chosen as endpoints for visual assessment, and the grouping of both NF1-associated and sporadic OPGs together, make it difficult to identify risk factors for visual outcome. In prior studies, NF1-OPGs were less likely than sporadic OPGs to have associated visual impairment at diagnosis and to exhibit radiographic progression over time.22–24
While several studies suggest that the visual loss prior to OPG treatment is irreversible,3,11
we clearly document VA improvement in 32% of subjects and 22% of eyes. This is important information for families and has significant implications for treating physicians when making decisions. Given that half of our subjects initiated treatment within 4½ months of OPG diagnosis, our study population may differ from those of prior studies in the duration of visual loss prior to therapy, although this was not directly assessed. Thus, treating patients with recent visual loss prior to irreversible damage might result in better functional outcomes. In addition, we do not have a rate of VA improvement for untreated NF1-OPG patients for comparison. It has been reported in the literature that some patients with NF1-OPG and VA loss improve spontaneously, and this has been suggested as a reason to hesitate initiating chemotherapy in patients with vision loss. Given the rarity of this phenomenon, its potential impact on the rate of improvement seen in our study is likely to be minimal.
We identified several factors associated with poor visual outcomes despite treatment. These include age (<2 y or >5 y) and optic pallor at the time of treatment. The former finding is consistent with previous studies that reveal that young age is a poor prognostic factor for tumor progression; however, the age of highest risk is variably reported as less than 1, 2, or 5 years.10,19,25
In contrast, age >5 years was associated with worse progression-free survival in the seminal publication on the efficacy of vincristine and carboplatin for the treatment of newly diagnosed, progressive low-grade glioma.8
While the prognostic significance of age disappears in the per-subject multivariate analysis, there is a trend toward an association. In addition, in the per-eye evaluation, age >5 years remains prognostic. This discrepancy may be a reflection of sample size and points to the need for a larger prospective study to evaluate the contribution of age to VA outcome.
The predictive value of optic pallor is difficult to determine, given that pallor often occurs in patients with OPG and no visual deficits. It is possible that pallor is an indicator of preexisting damage and heralds subsequent vision loss. It is also conceivable that the degree of optic pallor is the important marker of visual outcome5
; however, we did not capture quantitative data on optic pallor.
Although prognostic factors for OPG progression have been assessed in numerous studies, the focus has been on radiographic tumor progression rather than visual outcomes. Tumor involvement in the most posterior portion (postchiasmatic) of the visual pathway has been associated with a higher likelihood of VA loss,26,27
although not all studies support this conclusion.28,29
In our univariate and multivariate analyses, tumor involvement of the optic tracts/radiations was significantly associated with progressive visual loss despite chemotherapy. Hypothalamic involvement did not confer a poor visual prognosis, consistent with its anatomic location outside of the visual pathway.
Particularly striking is the poor correlation between visual and radiographic outcomes. Utilizing a clear definition of radiographic response, only 34%–38% of subjects (depending on whether those with MR are considered to be stable or improved) had concordant visual and radiographic outcomes, while 7%–11% of subjects had one outcome improved while the other was worse. Several smaller series have noted similar disparate results,5,13,30
although a clear objective definition of radiographic response was not always reported in these studies.5,13
Our findings call into question the traditional oncology method of defining response simply in terms of changes in tumor size rather than incorporating functional outcomes. It is possible that our results are affected by the inherent difficulty of measuring OPG size reliably in NF1 patients, who often have concurrent non-neoplastic areas of hyperintensity on T2-weighted MRI sequences (formerly referred to as unidentified bright objects). This seems unlikely given our use of standardized oncology criteria to define tumor response and progression (minimum 25% change) and review of the MRI scans by a neuroradiologist at each participating site.
There appears to be little consensus regarding the indications for treatment in our study, despite the involvement of high-volume NF clinical centers with large patient populations. Although VA loss and tumor progression were the main reasons for treatment, a combination of factors drove the responsible physicians to treat in most cases. Whether these differences among centers are due to the weight that individual physicians place on certain factors, differences in the referral patterns, or institutional practice biases, they demonstrate the need for uniform criteria for treatment.
For this cohort of NF1-OPGs that required treatment, the need for treatment was apparent early, as the median time from diagnosis of OPG to the initiation of treatment in our cohort was less than 4½ months. Since more than65% of subjects initiated treatment within 1 year of diagnosis and approximately 85% within 3 years, we advocate that patients with newly diagnosed NF1-OPGs undergo neuro-ophthalmology and neuro-oncology evaluation every 3 months for the first year, every 6 months for the next 2 years, and yearly thereafter. The identification of late presentations of symptomatic OPG suggests that continued yearly evaluations for up to 8 years after OPG diagnosis may be warranted. The optimal frequency of neuro-imaging follow-up has yet to be determined.
The strengths of the present study include its large sample size, involvement of centers with clinical expertise in the treatment of children with NF1, uniform population of NF1-associated OPGs, standardized assessment time points, and quantitative, clearly defined visual outcomes that were applied consistently across all centers. However, given that our outcome assessments were performed at the completion of therapy, no comment can be made on the durability of visual response. Our study had a higher percentage of subjects younger than 2 years old who were inevaluable for VA outcome because of a lack of quantitative data, highlighting the difficulty in obtaining reliable vision examinations in very young children and the need to explore potential surrogate markers for acuity, such as optical coherence tomography.31
In addition, adequate data on most of the ancillary visual outcomes (visual fields, ocular alignment, etc) were lacking. This deficiency underscores the challenge inherent in retrospective evaluations of visual parameters that are not traditionally reported in a quantitative fashion.
In summary, our multicenter study identified several important findings with clear clinical importance. First, although visual outcomes after treatment with chemotherapy for NF1-OPG are not optimal, there are children who regain vision with treatment. Second, tumor involvement of the optic tracts/radiations is the most consistent prognostic factor for poor visual outcome. Third, the lack of correlation between visual and radiographic outcomes argues against the use of MRI response as the gold standard of treatment success for this tumor. Fourth, the lack of agreement on indications for treatment of OPG among the large centers participating in this study highlights the need for better standardization of the care of these patients. Fifth, the short interval from diagnosis to initiation of treatment in the majority of NF1-OPGs has implications for the intensity of follow-up. These observations provide the key questions that can only be adequately addressed with a prospective collaborative study involving neuro-oncologists and neuro-ophthalmologists, which would employ standardized visual assessment methods and clear definitions of visual outcomes and data acquisition time points.