Intratumoral Metabolic Heterogeneity of Cervical Cancer

Abstract

Purpose: Previous research has shown that the intertumoral maximum standardized uptake value (SUV Max ) of F-18 fluorodeoxyglucose (FDG)^positron emission tomography (PET) for cervical cancer predicts disease outcome. The purpose of this study was to evaluate the pretreatment intratumoral metabolic heterogeneity of FDG. Experimental Design: This is a prospective cohort study of 72 patients with International Federation of Gynecology and Obstetrics stages Ib1 to IVa cervical cancer treated with chemoradiation. Three-dimensional FDG-PET threshold tumor volumes were calculated using image segmentation and an adaptive thresholding method for the primary cervix tumor from the pretreatment FDG-PET/computerized tomography. Intratumor heterogeneity was obtained for each patient's cervical tumor by taking the derivative (dV/dT) of the volume-threshold function from 40% to 80%. The association between intratumoral heterogeneity and tumorspecific factors and patient outcomes were determined. Results: The mean cervix tumor SUV Max was 12.4 (range, 3.0-38.4). The mean differential tumor heterogeneity was -1.074 (range, -0.107 to -5.623).There was no association between dV/dTand SUV Max (R 2 = 0.069), but there was a relationship with dV/dT and tumor volume (R 2 = 0.881). There was no correlation of dV/dT with tumor histology (P = 0.4905). Heterogeneity was significantly associated with the risk of lymph node metastasis at diagnosis (P = 0.0009), tumor response to radiation as evaluated by FDG-PET obtained 3 months after completing treatment (P = 0.0207), risk of pelvic recurrence (P = 0.0017), and progression-free survival (P = 0.03). Conclusions: Cervical intratumoral FDG metabolic heterogeneity on the pretreatment FDG-PET predicts risk of lymph node involvement at diagnosis, response to therapy, and risk of pelvic recurrence.It is understood that, on a microscopic level, tumors are heterogeneous (1 -3). Evaluation of tumor microenvironments has shown heterogeneity relating to variation in tumor responsiveness to treatment (4, 5), degree of vascularity (6, 7), hypoxia (1, 7, 8), proliferation rates (7), energy metabolites, and gene expression (9 -11). Although tumor heterogeneity has been shown within these tumor microenvironments, intratumoral heterogeneity across the entire volume of primary tumors in humans has not been quantified or analyzed for its association with outcome measures. F-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging allows intratumoral heterogeneity to be assessed using objective criteria.Cervical cancer is an example of a tumor that shows heterogeneity relating to hypoxia, variation in response to treatment, risk of metastatic spread, and gene expression (4, 5, 10, 12 -15). Additionally, the response of the primary cervical cancer to treatment has been shown to be a much more complex issue than simply relating outcome to clinical stage, tumor volume, or tumor hypoxia. Specifically, our previous research has shown that the primary cervix tumor maximal standardized uptake...

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“…The intratumoral metabolic heterogeneity was represented by the heterogeneity factor (HF) [16], which was determined for each patient as follows: a region of interest (ROI) was manually drawn to fully include the primary tumor and a surrounding region of normal tissue (normal background). The tumor volume was determined with a series of SUV thresholds (e.g., 40%, 50%, 60%, 70%, and 80% of SUVmax) using the semiautomatic software of the workstation (Advantage Workstation 4.3, GE Healthcare).…”

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“…More specifically, in two studies in cervical cancer a metric based on a “volume versus threshold curve” was not able to predict outcome in 73 patients [67], contradicting a previous assessment in the same cohort [70]. Although other first-order features such as standard deviation, skewness and kurtosis were also included, it should be emphasized that this study essentially highlighted the fact that the metric based on the “volume versus threshold curve” is a surrogate for volume, not a measurement of heterogeneity (see also Supplementary material).…”

The biology underlying molecular imaging in oncology: from genome to anatome and back again

“…In cervical cancer, the inter-tumoral maximum value of FDG uptake (SUV Max ) has been shown to be predictive of outcome. However, more recent studies have shown that SUV heterogeneity was more predictive of lymph node metastasis at diagnosis and radiation response and progression-free survival (34). In this study, volumes were derived using adaptive image segmentation and using the pretreatment FDG-PET/CT images.…”