Radiation therapy (RT), with or without chemotherapy, is the standard of care in locally advanced cervical cancer. Typically, response assessment takes place about two to three months post treatment which makes it too late to change treatment strategy for non-responders. This study aims to evaluate early tumor response by serial 18F-FDG integrated PET/MRI during treatment by qualitative and semi-quantitative comparison of changes in anatomical and functional parameters to assess whether any parameters can be used as independent prognostic markers for complete response and disease-free survival.

This study was approved by Singapore NHG Domain Specific Review Board. Three patients with histopathologically confirmed cervical cancer and undergoing RT were enrolled in this prospective pilot study. All patients received five and half weeks of daily external RT and four or five insertions of ring (Vienna) or ovoid (Utrecht) based brachytherapy. Four multi-parametric PET/MRI scans including dynamic contrast-enhance imaging (DCE) and diffusion weighted imaging (DWI) were performed on each patient with written informed consent. The first scan was obtained at baseline before treatment with 6mCi 18F-FDG, the second and the third scans were performed just before the first and the third brachytherapy insertions respectively with 3mCi 18F-FDG and the fourth scan was done three months post treatment with 6mCi 18F-FDG. The images were acquired on Biograph mMR 3T PET/MRI (Siemens Healthcare). All patients fasted for at least six hours prior to each examination. Pelvic PET images were acquired 60 minutes post injection. Gadolinium was used for DCE imaging.

The tumor lesions were contoured on T2-weighted MR images and automatically mapped onto the inherently co-registered DCE, DWI and PET images. For the later time-points when the lesion had shrunk, a contour from a previous time-point was registered to the current time-point using an image registration framework developed in-house [1]. Tumor volume, mean apparent diffusion coefficient (ADC) using b-values of 100 and 800, the maximum and mean standardized uptake values (SUV), metabolic target volume (MTV), total lesion glycolysis (TLG) and Ktrans within the tumor sub-volume were analyzed over the four time-points. For SUV, the PET images were reconstructed using the iterative ordered-subset expectation maximization algorithm, three iterations and 21 subsets, a Gaussian filter with 3.0 mm full width at half maximum and a 344x344 image matrix. Automatic attenuation correction was performed based on a four-compartment-model attenuation map. MTV was obtained by applying a 40% of SUVmax iso-contour.

Two patients have completed all four scans and one patient is awaiting the last scan. Significant reductions in tumor volume, MTV, SUV and TLG was observed between the baseline and the second scans (Table 1). For one patient, there was a mid-treatment increase in SUV. This patient had interstitial needle insertion as well during intracavitary brachytherapy. The increase in SUV could also be attributed to confounding peri-tumoral inflammation after brachytherapy and the increasing proximity of the tumor to the bladder resulting in ROI mapping errors. For two patients, mean ADC increased by more than 80% between the first and the second scans and then came down to below 60% above baseline on the third scan. However, for the one patient who had an increase in SUV mid-treatment, the mean ADC dropped by 28% on the second scan and came back up only to 6% below baseline by the last scan. Consistent patterns of alterations in the DCE parameters during treatment is yet to be observed which is similar to [2]. Correlations between various parameter changes is shown in figure 2. Figure 3. shows a sample metabolite spectrum from a tumor lesion. We observe most significant reductions in tumor volumes, MTV and TLG between baseline and post external beam radiotherapy. Tumor uptake is expected to decrease with treatment and the ADC values are expected to increase. However, in one case we observe that the SUV values increased during treatment and ADC values decreased. This early findings from the first three subjects provide interesting results and press the need for a future study with larger datasets.By assessing early tumor response while within the treatment, this study hopes to facilitate treatment changes early, such as dose escalation using brachytherapy or surgery after completion of RT in cases where RT is ineffective in achieving complete response.