Single- and Multi-Fraction Stereotactic Radiosurgery Dose Tolerances of the Optic Pathways

Abstract

Purpose: Dosimetric and clinical predictors of radiation-induced optic nerve/chiasm neuropathy (RION) after single-fraction stereotactic radiosurgery (SRS) or hypofractionated (2-5 fractions) radiosurgery (fSRS) were analyzed from pooled data that were extracted from published reports (PubMed indexed from 1990 to June 2015). This study was undertaken as part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy, investigating normal tissue complication probability (NTCP) after hypofractionated radiation.

Methods and materials: Eligible studies described dose delivered to optic nerve/chiasm and provided crude or actuarial toxicity risks, with visual endpoints (ie, loss of visual acuity, alterations in visual fields, and/or blindness/complete vision loss). Studies of patients with optic nerve sheath tumors, optic nerve gliomas, or ocular/uveal melanoma were excluded to obviate direct tumor effects on visual outcomes, as were studies not specifying causes of vision loss (ie, tumor progression vs RION).

Results: Thirty-four studies (1578 patients) were analyzed. Histologies included pituitary adenoma, cavernous sinus meningioma, craniopharyngioma, and malignant skull base tumors. Prior resection (76% of patients) did not correlate with RION risk (P = .66). Prior irradiation (6% of patients) was associated with a crude 10-fold increased RION risk versus no prior radiation therapy. In patients with no prior radiation therapy receiving SRS/fSRS in 1-5 fractions, optic apparatus maximum point doses resulting in <1% RION risks include 12 Gy in 1 fraction (which is greater than our recommendation of 10 Gy in 1 fraction), 20 Gy in 3 fractions, and 25 Gy in 5 fractions. Omitting multi-fraction data (and thereby eliminating uncertainties associated with dose conversions), a single-fraction dose of 10 Gy was associated with a 1% RION risk. Insufficient details precluded modeling of NTCP risks after prior radiation therapy.

Conclusions: Optic apparatus NTCP and tolerance doses after single- and multi-fraction stereotactic radiosurgery are presented. Additional standardized dosimetric and toxicity reporting is needed to facilitate future pooled analyses and better define RION NTCP after SRS/fSRS.

Figure 1.

Summary of radiation-induced optic neuropathy (RION) data. The reported crude rate of RION is plotted (as a probability) is plotted against the reported optic nerve/chiasm median maximum dose for studies with all patients completing treatment prior to 1997 (A); and for studies where some or all patients were treated during or after 1997 (B). The size of each data point reflects the number of patients analyzed (not a reflection of the error or uncertainty of data). In panel B, also shown below the x-axis are the maximum doses resulting in RION; each data point (square or round as described below) represents 1 event. Patients who had received no prior radiotherapy (hollow shapes) are shown separately from patients who had received prior radiotherapy (solid shapes), as are patients treated with single-fraction radiosurgery (SRS; circles) and patients treated with 2–5 fraction radiosurgery (fSRS; squares).

Figure 1.

Summary of radiation-induced optic neuropathy (RION) data. The reported crude rate of RION is plotted (as a probability) is plotted against the reported optic nerve/chiasm median maximum dose for studies with all patients completing treatment prior to 1997 (A); and for studies where some or all patients were treated during or after 1997 (B). The size of each data point reflects the number of patients analyzed (not a reflection of the error or uncertainty of data). In panel B, also shown below the x-axis are the maximum doses resulting in RION; each data point (square or round as described below) represents 1 event. Patients who had received no prior radiotherapy (hollow shapes) are shown separately from patients who had received prior radiotherapy (solid shapes), as are patients treated with single-fraction radiosurgery (SRS; circles) and patients treated with 2–5 fraction radiosurgery (fSRS; squares).

Figure 2.

Kaplan-Meier (KM) analysis of the cumulative probabilities of RION among patients with no prior radiotherapy. KM analyses used follow-up data when available and median optic apparatus maximum dose, with events scored at the time of occurrence, and at the doses which events occurred. When no detailed actuarial data was available, the timings of all complications in the cohort were assigned as the median length of follow-up.” (Online Table 3). Separate KM curves are shown for optic apparatus maximum single-fraction equivalent doses of <12 Gy and ≥12 Gy (EQD2_1.6=45.3 Gy, depicted as “12 Gy” in figure), grouped by inclusion of all studies or only studies which included some or all patients treated during or after 1997 (1997+ studies).

Figure 3.

Results of the model fit to the available data from the 1997+ studies (those including some or all patients treated during or after 1997), and with no prior radiotherapy. Dose-response for radiation-induced optic neuropathy estimated using the probit model. (A) Patients treated with single-fraction stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiosurgery (fSRS). (B) Only patients treated with a single-fraction stereotactic radiosurgery (SRS). Maximum optic apparatus doses resulting in RION in individual patients were identified in all studies that reported RION events (Figure 1 and Online Table 3). For patients not developing RION, maximum doses were extracted in the most granular groupings possible (i.e. individual patients vs. patients grouped by maximum dose vs. median/mean of the maximum dose for the entire study cohort). This data was binned into 5 dose groups, with NTCP calculated for each binned group, and are depicted as the 5 data points with associated error bars. Confidence intervals for the NTCP curve were calculated using Agresti’s approximation. While the maximum doses were reported for all of the cases with complications, the doses reported for most of the cases without complications were only provided as medians or quartiles. To deal with this uncertainty, two methods of calculating a dose response were used. The inverse variance weighting method groups patients together and weights these data points by patient numbers in each group. This loses resolution in dose for the complications. The maximum likelihood approach method weights the response using individual patient data when available. However, when a dataset only provides the median dose of the non-complications cases, but the spread of non-complications cases includes higher doses in the vicinity of the complications cases, the maximum likelihood algorithm has no way to account for this. Consequently the complications may be overemphasized and a more conservative dose response results. The dashed (more superior) curve depicts direct likelihood fitting; dotted lines show the 95% confidence band reflecting the uncertainty in the data. The solid (more inferior) curve depicts the adjusted model, using effective inverse variance weighting. For illustrative purposes, the maximum doses resulting in RION events are shown as 100% NTCP points, while the points at 0% NTCP points reflect those patients who did not experience RION. The plot shows the 1%, 2% and 5% NTCP risks (from the model adjusted for using effective inverse variance weighting). In (A) these 1%, 2% and 5% NTCP risks are shown as a function of biologically effective dose (EQD2_1.6; equivalent dose at 2 Gy/fraction assuming α/β=1.6 Gy), the corresponding biologically equivalent dose (BED_1.6), and 1, 3, 5 fractions (Fx) equivalent doses (Deq; also computed assuming α/β=1.6 Gy).

Figure 3.

Results of the model fit to the available data from the 1997+ studies (those including some or all patients treated during or after 1997), and with no prior radiotherapy. Dose-response for radiation-induced optic neuropathy estimated using the probit model. (A) Patients treated with single-fraction stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiosurgery (fSRS). (B) Only patients treated with a single-fraction stereotactic radiosurgery (SRS). Maximum optic apparatus doses resulting in RION in individual patients were identified in all studies that reported RION events (Figure 1 and Online Table 3). For patients not developing RION, maximum doses were extracted in the most granular groupings possible (i.e. individual patients vs. patients grouped by maximum dose vs. median/mean of the maximum dose for the entire study cohort). This data was binned into 5 dose groups, with NTCP calculated for each binned group, and are depicted as the 5 data points with associated error bars. Confidence intervals for the NTCP curve were calculated using Agresti’s approximation. While the maximum doses were reported for all of the cases with complications, the doses reported for most of the cases without complications were only provided as medians or quartiles. To deal with this uncertainty, two methods of calculating a dose response were used. The inverse variance weighting method groups patients together and weights these data points by patient numbers in each group. This loses resolution in dose for the complications. The maximum likelihood approach method weights the response using individual patient data when available. However, when a dataset only provides the median dose of the non-complications cases, but the spread of non-complications cases includes higher doses in the vicinity of the complications cases, the maximum likelihood algorithm has no way to account for this. Consequently the complications may be overemphasized and a more conservative dose response results. The dashed (more superior) curve depicts direct likelihood fitting; dotted lines show the 95% confidence band reflecting the uncertainty in the data. The solid (more inferior) curve depicts the adjusted model, using effective inverse variance weighting. For illustrative purposes, the maximum doses resulting in RION events are shown as 100% NTCP points, while the points at 0% NTCP points reflect those patients who did not experience RION. The plot shows the 1%, 2% and 5% NTCP risks (from the model adjusted for using effective inverse variance weighting). In (A) these 1%, 2% and 5% NTCP risks are shown as a function of biologically effective dose (EQD2_1.6; equivalent dose at 2 Gy/fraction assuming α/β=1.6 Gy), the corresponding biologically equivalent dose (BED_1.6), and 1, 3, 5 fractions (Fx) equivalent doses (Deq; also computed assuming α/β=1.6 Gy).