ABSTRACT
Gynecologic cancers are among the leading causes of cancer death in women worldwide. These
patients typically are socioeconomically disadvantaged, with poor access to screening and vaccination.
Consequently, they often present with locoregionally advanced disease, for which pelvic radiotherapy (RT) with
concurrent cisplatin (i.e., chemoradiotherapy) is the standard of care. This treatment is limited, however, by
high rates of treatment failure. Intensifying treatment through the delivery of chemotherapy doublets, either
concurrently or as adjuvant therapy following chemoradiotherapy, is a promising strategy to improve outcomes.
However, the delivery of intensive chemotherapy is complicated by high rates of gastrointestinal and
hematologic toxicity. Strategies to reduce toxicity while increasing efficacy of chemoradiotherapy are needed.
Standard pelvic RT techniques encompass large volumes of normal tissue including bowel, bone
marrow, bone, bladder, and rectum, leading to preventable radiation-induced toxicity. Image-guided radiation
therapy (IGRT) can improve target localization and dosimetry, optimizing target dose while minimizing dose to
surrounding normal tissues. However, IGRT can be highly resource intensive, and comparative effectiveness
trials have been lacking. For this reason, there is considerable controversy as to the utility of IG-IMRT in this
disease. Our research group has been at the forefront of developing novel, cost-effective IGRT approaches
with wide potential to facilitate better delivery of concurrent and/or adjuvant chemotherapy.
Previously we have found that radiation-induced injury to hematopoietically active bone marrow is a
critical determinant of tolerance to intensive chemotherapy. Using machine learning methods, we recently
developed a multi-atlas-based IGRT method that can predict canonical distributions of active bone marrow,
which can obviate the need for positron emission tomography (PET) in settings where this technology is
unavailable or unaffordable. The proposed new research will study the ability of multi-atlas-based IGRT to
reduce hematologic toxicity and improve chemotherapy delivery compared to standard treatment, using data
from 450 patients enrolled to a randomized phase III trial (NRG-GY006). Furthermore, we will use serial whole
body PET/CT to study the impact of radiation dose and chemotherapy intensity on the compensatory
hematopoietic response, and have developed novel whole body radiomics biomarkers to quantify the
inflammatory state, which we hypothesize can influence patients' outcomes and tolerance to chemotherapy.
The new research extends our work associated with a current R01 grant (1R01CA197059-01) to
conduct correlative science associated with the GY006 trial. The overarching goal of this research line is to
augment the therapeutic ratio of chemoradiotherapy for pelvic cancers using advanced image-guided radiation
techniques. If successful, this research would significantly alter the approach to the treatment of many pelvic
malignancies for which chemoradiotherapy is standard.