Clinical controversies: proton therapy for pediatric tumors

Abstract

Despite the claim in the published literature, the introduction of proton therapy for children is not analogous to the evolution of conformal photon irradiation relying on the understanding of the impact of altered dose distributions. The differences in radiobiological effect when comparing photons with protons mean that we are comparing a known entity with an unknown entity: the dose-volume histogram for proton therapy might mean something substantially different from the dose-volume histogram for photon therapy. The multifaceted difference between the 2 modalities supports the argument for careful evaluation, follow-up, and clinical trials with adverse event monitoring when using proton therapy in children. We review the current data on the outcome of proton therapy in a range of pediatric tumors and compare them with the often excellent results of photon therapy in the setting of multidisciplinary management of childhood cancer. It is hoped that the apparent dosimetric advantage of proton therapy over photons will lead to improved indications for therapy, disease control, and functional outcomes. Although physical dose distribution is of clear importance, the multimodality management of children by an expert pediatric oncology team and the availability of ancillary measures that improve the quality of treatment delivery may be more important than the actual beam. In addition, current estimates of the benefit of proton therapy over photon therapy based on toxicity reduction will only be realized when survivorship has been achieved. Once substantive proton therapy data become available, it will be necessary to demonstrate benefit in clinically relevant outcome measures in comparison with best existing photon outcome data. Such an effort will require improved funding and appreciation for late effects research. Only real clinical outcome data combined with better understanding of the radiobiological differences between protons and photons will help us to further reduce side effects in children and exploit the full curative potential of this relatively new modality.

Figure 1

Children treated with proton therapy in 2010 (adapted from presentation at www.pediatricprotonfoundation.org). Legend: MB/PNET, medulloblastoma/primitive neuroectodermal tumor; EP, ependymoma; RMS, rhabdomyosarcoma; ES, Ewing sarcoma; ATRT, atypical teratoid rhabdoid tumor; CGT, CNS germ cell tumor; NB, neuroblastoma; NRSTS, non-RMS soft tissue sarcoma.

Figure 2

Wechsler Individual Achievement Test (WIAT) mathematics scores estimated 5 years after treatment for children with craniopharyngioma using whole-brain integral dose data from the MD Anderson Cancer Center comparative dosimetry study (Boehling 2012) and St. Jude Children’s Research Hospital cognitive effects models (Merchant 2011). Legend: CSF, cerebrospinal fluid; IMRT, intensity-modulated radiation (photon) therapy; 3DPT, 3-dimensional (passively-scattered) proton therapy; IMPT, intensity-modulated proton therapy.

Figure 3

Craniospinal dose distribution planned for a pediatric case of medulloblastoma using intensity-modulated proton therapy.

Figure 4

Simulated intensity-modulated photon therapy (IMRT) and intensity-modulated photon therapy (IMPT) mean brain dose data and published cognitive models (Merchant et al., Int J Radiat Oncol Biol Phys 65:210:2006).

Figure 5

Double-scattered proton therapy (left) and intensity-modulated photon therapy (right) treatment plans for a child with infratentorial ependymoma. Legend: Whole-brain dose volume histograms (yellow); cochlear dose volume histograms (light blue=photon, magenta-proton); hypothalamus (green).

Figure 6

Double-scattered proton therapy plan for a pelvic Ewing sarcoma in a female patient.

Figure 7

Examples of conventional (mantle), involved-field, and involved-nodal treatment volumes for Hodgkin Lymphoma and photon and proton therapy dose distributions.