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 al...