PhD defense by Daniel Gram

Minimizing side effects for pediatric patients treated with craniospinal irradiation

Second only to leukemia, primary tumors in the central nervous system (CNS) are the most commonly occurring malignancies in children, with medulloblastoma being the most prevalent. The standard-of-care for medulloblastoma consists of a combination of surgery, chemotherapy and craniospinal irradiation (CSI) and is usually administered to children above 3-5 years of age. Pediatric CNS tumors, although rare, have a devastating impact on patients and their families both due to the disease and the severe treatment related side effects. Most long-term survivors of malignant pediatric CNS tumors treated with CSI have significant late effects, such as perturbed growth, hearing or vision loss, cardiovascular events, lung toxicity and neurocognitive impairment, and patients irradiated at a younger age tend to have worse outcomes. Since the frequency and severity of late side effects generally increase with time, they are especially debilitating for pediatric cancer survivors as they mature into adulthood.

The purpose of this PhD project was to investigate different possibilities of reducing side effects to organs-at-risk (OARs) for pediatric patients with CNS malignancies treated with CSI. We investigated setup errors and uncertainties to evaluate margins and robustness perturbations needed for CSI treatments. These results were used to create realistic hippocampal-sparing proton therapy treatment plans aimed at reducing neurocognitive impairment. The results from that study demonstrated that it is possible to reduce the risk of neurocognitive impairment with only a minimal impact on target coverage and without reducing the estimated tumor control. We further investigated the effects of linear energy transfer (LET) and how it impacts the radiobiologically weighted dose distribution generally and how these results affect the sparing of the hippocampi specifically. We found that areas of where the proton beam stops can be highly affected depending on the tissue specific parameters assigned to the tumor and OARs. This field of study needs further investigation before biologically weighted doses can be used clinically, especially in the setting of hippocampal-sparing (HS) CSI. We also created mathematical models for predicting OAR doses from spinal irradiation treatments delivered in the era before 3D treatment planning and volumetric dose reporting. The aim of this was to be able to link OAR doses with longterm follow-up data for an increased understanding of dose-response relationships in cohorts of pediatric cancer survivors, which could further reduce the side effects to this patient group.
The work conducted and results presented in this thesis show that there are actionable opportunities for minimizing side effects of pediatric patients with CNS malignancies treated with CSI.

A printed version of the thesis is available for the audience at the PhD defense on October 21, and hereafter can be obtained at Rigshospitalet, Blegdamsvej 9, opgang 39, onkologisk klinik, afsnit for stråleterapi (3993/3994). A digital version is available in .pdf upon request from mail to:

Join Zoom Meeting

Meeting ID: 645 0460 5074

Passcode: 660412