Summary
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The functional and biological properties of the tumor microenvironment are fundamentally important determinants of tumor response and therapy outcome in cancer. Oxygenation status and vascularity and are known to influence radiation response, and molecular energy metabolism and proliferation impact on recurrence and metastatic progression. However, with the current standard clinical diagnostic approaches, such as biopsy or anatomic/morphologic tumor imaging, assessment of the known intra-tumoral heterogeneity of functional and biological tumor properties is limited. Specifically, the functional characteristics within the microenvironmental environment throughout the entire tumor have been challenging to assess spatially for tumor heterogeneity and temporally for clinical correlation before and during treatment. While histologic tissue sampling is widely used clinically, sampling of the entire tumor with extensive biopsies, or biopsies at various time points during therapy for intra-treatment assessment are impractical and generally pose unacceptable clinical risk. Functional/molecular imaging offers the opportunity to assess biological heterogeneity across the entire tumor volume (spatially) and longitudinally across the treatment course (temporally). In advanced cervical cancer, the tumor gradually undergoes radiation/chemotherapy induced functional and biological changes within its heterogeneous volume that can be assessed by sequential imaging before and during treatment. Advanced cervical cancer is an ideal disease to study – in clinical patients – the vascular, cellular and molecular tumor properties that can provide essential information to monitor therapeutic responsiveness, facilitate treatment planning and may provide early prediction of ultimate success or failure of an ongoing treatment. Advanced cervical cancer is treated with cytotoxic therapy: radiation and concurrent chemotherapy. It is a highly prevalent disease globally, and treatment failure is common. The propensity of cervical cancer for hypoxia and poor vasculature within the often bulky heterogenous tumor volume is well-recognized. Because advanced cervical cancer is not surgically resected, functional/molecular imaging provides unique opportunities for non-invasive assessment across the treatment course This proposal seeks to share prospectively performed functional/molecular imaging data sets (performed on an NCI funded R01) in patients with advanced cervical cancer, who were treated with standard combined radiation therapy and chemotherapy. Both, functional typically dynamic contrast enhanced (DCE), diffusion-weighted (DWI) MRI and 18FDG PET/CT were obtained in patients with advanced cervical cancer at 4 prospectively designed time points/radiation dose levels: before treatment start (dose 0), early during the treatment course (2-2.5 weeks after treatment start/dose 20-25 Gy), at mid-treatment (4-5 weeks after treatment start/dose 45-50 Gy) and 1 month after completion of all radiation therapy/concurrent Cisplatin chemotherapy therapy (the current standard of care). There are a total of 7 studies per patient: 4 MRI and 3 PTE/CT data sets. This prospective imaging data provides heterogeneity imaging assessment of the tumor volume (cervical cancer) with both functional MRI and 18FDG PET in parallel. The resulting imaging data sets allow detailed study of the evolution of functional/molecular tumor heterogeneity before, across and after completion of the radiation therapy course. This is a unique data set (not available elsewhere to our knowledge). The prospectively obtained and standardized imaging is not only timed according to the radiation dose level and time course, but also correlated with ultimate the treatment outcome (tumor response, local tumor control, survival). Cervical cancer is an ideal model to study vascular, cellular and molecular tumor properties across the radiation treatment course as the tumor undergoes radiation-induced functional/biological changes within its heterogeneous volume. The understanding of such biological processes occurring during the radiation course remains a major knowledge gap in radiation oncology. Such phenomena are challenging to study with histologic biopsy due to the inability to sample the entire tumor, and due to the challenge and risk in performing multiple tumor biopsies during radiation therapy in clinical patients. In contrast functional/molecular imaging can assess this biological heterogeneity encompassing the entire tumor volume. Our study does so longitudinally across the time course of radiation therapy. These intra-treatment functional phenomena may translate into important actionable imaging biomarkers of long-term treatment outcome. For example, vascular tumor properties (as identified by DCE MRI) are highly significant for tumor oxygenation, which in turn profoundly influences radiation response. For example, our early investigations suggest that typically dynamic contrast enhancement (indicative of tumor microvasculature) improves early in the treatment course and heterogeneity decreases, particularly in responders; while FDG heterogeneity tends to show reduced metabolic activity that becomes evident later in the radiation treatment course. Our imaging data in cervical cancer may complement the TCIA's existing disease portfolio, which currently to our knowledge contains only one other collection in cervical cancer (imaging–genomic atlas). We believe our functional/molecular imaging data set can serve a unique resource, that should be made available to the wider scientific community, so that it will continue to be available to longitudinally (across a cytotoxic therapy course) interrogate sequential functional and molecular tumor properties – well into the future as image analysis and radiomics techniques will continue to advance, well beyond the time course of our own studies. Translation to clinical practice: The imaging sequences, while complex and functional, were designed upfront such that they are translatable and widely applicable to community settings. This is important because cervical cancer is a disease largely treated in the community setting, often in underserved communities. |
Acknowledgements
Data was supported in part by NCI grant R01CA155454. Foundational and pilot data, which enabled the work on R01CA155454 and on this collection, were supported by R01CA71906.
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