Risk And Risk Factors For Colorectal Subsequent Malignancies In Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study

Author

Constance A. Owens, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

0000-0001-7208-394X

Date of Graduation

8-2023

Document Type

Dissertation (PhD)

Program Affiliation

Medical Physics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Rebecca M. Howell, PhD

Committee Member

Kristy K. Brock, PhD

Committee Member

Stephen F. Kry, PhD

Committee Member

Arnold de la Cruz Paulino, MD

Committee Member

Christine B. Peterson, PhD

Abstract

Survivors of childhood cancer are at risk for colorectal subsequent malignant neoplasms (SMNs); notably, these cancers are amenable to screening. To identify at-risk survivors that may benefit from early screening, descriptive and risk factor analyses were performed to ascertain risk factors for colorectal SMN in childhood cancer survivors. In particular, we explored detailed radiation therapy (RT) data – colorectal and substructure dose-volume metrics – as risk factors for colorectal SMN risk; metrics that have yet to be thoroughly investigated. We developed a novel population-based anatomical colorectal model with substructures for RT dosimetry in late effects studies of childhood cancer survivors; unique to this anatomical model is the incorporation of anatomical variations of 103 unique pediatric patients. We dosimetrically validated the colorectal model and used it calculate whole colorectal and substructure RT doses for survivors from the Childhood Cancer Survivor Study (CCSS). The CCSS is a cohort study that currently consists of 25,725 survivors of which 13,147 received RT for their primary cancer diagnosis and 104 have been diagnosed with a colorectal SMN. These detailed organ-specific RT metrics were included in dose-response models for predicting colorectal SMN risk in the CCSS. We provided an update of risks and associated risk factors for colorectal SMN risk in the CCSS with demographic, behavioral and treatment exposure factors including the first reporting of detailed organ-specific RT metrics. We developed a pediatric population-based age-scalable colorectal model with substructures and demonstrated its dosimetric performance for accurate pediatric RT dose reconstruction. In multivariable analysis whole colorectum mean RT doses above 10Gy (similar trends were observed for the substructure analysis) and max dose above 30Gy was associated with increased risk of colorectal SMN. For each dose-volume metric, colorectal SMN risk increased in a dose-dependent manner with increasing volume of colorectal irradiated above 20% volume. For the chemotherapy associations, risk increased for alkylating doses above 6,683mg/m2 CED, however the risk remained relatively consistent for the higher dose categories. To date, this is the largest and first childhood cancer survivor study to stratify colorectal SMN risk with this level of detail for either RT mean dose, dose-volume metrics or alkylating agent dose.

Keywords

Subsequent malignancies, childhood cancer, late effects, cancer epidemiology, dose reconstruction, computational phantom, radiation therapy, radiation-related late effects