National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury

Abstract

Purpose: Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury.

Methods and materials: Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016.

Results: The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning.

Conclusions: Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.

Figure 1

Two IMPT plans that display clinically equivalent dose distributions, but different LET distributions. (Chordoma; dose in % of prescribed dose; GTV line in blue. The right column shows the mean LET_d distributions in kev/µm).

Figure 2

University of Florida. Ependymoma proton treatment example with 59.4 CGE prescribed to the clinical target volume CTV (yellow). Left: Initial phase 54.0 CGE, (red dose-wash), priority is given on target coverage. Middle: Reduction phase 5.4 CGE (blue dose-wash), priority is given to brainstem sparing. And Right: Composite dose distribution, 59.4 CGE (red dose-wash). Target volume is depicted in yellow contour.

Figure 3

Dosimetry for the MGH patient (see Fig. 5) if the brainstem RBE = 1.1 (top dosimetry panels) or 1.2 (bottom dosimetry panels) while for other tissues RBE = 1.1

Figure 4

MGH: Right oblique for the total CTV (purple, left) up to 50.4 and cone down (right) at the cord / brainstem junction. Also shown are the cochlea, pituitary and hypothalamus. Often, but not in this case, the aperture is tightened along the brainstem surface to reduce dose to the brainstem in the cone-down as applied in the UF treatment parameters shown in Table 2.

Figure 5

MGH. Transverse and sagittal proton dose distributions. Note the 52 Gy (RBE) isodose at the cord (cyan) / brainstem (green except in GTV / CTV overlap) junctions. A few hotspots of 55 Gy (RBE) are also observed.

Figure 6

MGH. DVH for the patient shown in Fig. 5. Note the GTV / CTV dose deficit dictated by the spinal cord constraint and the sharp fall-off of dose for the targets and brainstem.

Figure 7

MDACC:The left transverse, sagittal and coronal panels show the primary course dose using 2 posterior oblique fields and a vertex field to 50.4 Gy (RBE). The right panels show the boost of 3.6 Gy (RBE) and indicate the dose reduction to the spinal cord. Prescription dose levels, 50.4 on the left group of three images and the boost of 3.6 Gy (RBE) on the right set of three images, are in green.