Risk of Secondary Malignant Neoplasms in Children Following Proton Therapy vs. Photon Therapy for Primary CNS Tumors

Abstract

<h3>Purpose/Objective(s)</h3> Central nervous system tumors are the second most common primary neoplasms seen in children and radiation therapy is a key component in management of most of these tumors. Secondary malignant neoplasms (SMNs) are rare but dreaded complications, particularly in the pediatric population. Proton beam therapy (PBT) can potentially minimize the risk of SMNs compared to conventional photon radiation therapy (RT). Multiple recent studies with mature data have reported the risk of SMNs after PBT. We performed this systematic review and meta-analysis to characterize and compare the incidence of SMNs after proton and photon-based radiation for pediatric CNS tumors. <h3>Materials/Methods</h3> A systematic search of literature on electronic (PubMed, Cochrane Central, and Embase) databases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We included studies reporting incidence and nature of SMNs in pediatric patients with primary CNS tumors. The crude incidence of SMNs and all secondary neoplasms were separately extracted, the random-effects model was used for pooled analysis and subgroup comparison was performed between studies using photons vs protons. <h3>Results</h3> Twenty-four studies (21 with conventional RT and 4 with PBT) were included for meta-analysis after performing the systematic review. A total of 418 SMNs and 645 any secondary neoplasms were seen in 38163 patients overall. The most common secondary neoplasms seen were gliomas (40.6%) followed by meningiomas (38.7%), sarcomas (4.8%), thyroid cancers (4.2%), and basal cell carcinomas (1.3%). The overall median follow-up was 8.8 years (range: 3.3 to 23.2 years), while the median latency to a secondary cancer was 9.8 years (range: 5 to 23 years). The median latency to a secondary cancer for photons and protons was 11.9 years (range: 5 to 23 years) and 5.9 years (range: 5 to 6.7 years), respectively. The pooled incidence of SMNs was 1.8% (95% CI: 1.1% – 2.6%, I²=94%) with photons and 1.5% (95% CI: 0 - 4.5%, I²=81%) with protons. There was no significant difference among the two subgroups (p = 0.91). Similarly, the pooled incidence of all secondary neoplasms was not different among the two subgroups [photons: 3.6% (95% CI: 2.5% – 4.8%, I²=96%) vs protons: 1.5% (95% CI: 0 – 4.5%, I²=80%); p = 0.21]. <h3>Conclusion</h3> We observed a slightly lower rate of SMN with PBT at 1.5% compared to 1.8% with photon-based RT for pediatric CNS tumors, although the difference was not statistically significant. We observed a shorter latency to secondary cancers with proton therapy compared to photon-based radiation, which may be related to secondary neutron exposure. With increasing use of techniques that decrease the irradiated tissue volume outside the clinical target volume, like pencil beam scanning proton therapy and VMAT, further studies with longer follow-up are warranted to evaluate the risk of secondary cancers in patients treated with these newer modalities.