## 4 Discussion  
The conventional parameters used in the nuclear medicine environment, such as the SUV\({}_{\text{max}}\), can be affected by statistical fluctuation errors and cannot provide information on the tumor extension and heterogeneity. The other parameters introduced to resolve these limitations have some limitations related to partial volume effect [32] and to the segmentation method chosen to identify the tumor area [37]. TLG is the first parameter that can provide both anatomical and metabolic information. It is calculated by performing a multiplication of SUV\({}_{\text{mean}}\) with the MTV value. Nevertheless, TLG does not take into account the SUV distribution within the VOI. New parameters were proposed, such as CSH and AUC, in order to provide information about the absolute uptake, the radiotracer distribution, and the lesion dimension [22; 33; 38; 39]. The histograms are similar to DVH used in radiotherapy [30]. The CSH is a cumulative histogram that shows the percentage of the lesion volume with the same SUV. It takes into account the distribution of SUV within the tumor volume. The AUC consists of the value of the area under the histogram curve and can be a quantitative index of tracer uptake heterogeneity or homogeneity tumor response [22]. The aim of this work was to assess these new prognostic indices in order to perform an early assessment of the treatment response to therapy using MET-PET images. The strength of these new parameters is that they can potentially take into account the SUV distribution within the tumor area voxel by voxel and not only a single one, as is the case when using SUV\({}_{\text{max}}\) or a single mean value, i.e., the SUV\({}_{\text{mean}}\), which does not take into account the tumor heterogeneity. No relevant correlation was found between AUC and  
Figure 8: On the left: CSH pretreatment (top left); CSH post-treatment (top right); comparison between pre- and post-treatment (bottom) in negative response case: \(\Delta\text{AUC}=8.62\%\). On the right: PET images of pre- and post-treatment. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Figure 7: On the left: CSH pretreatment (top left); CSH post-treatment (top right); comparison between pre- and post-treatment (bottom) in stable response case: \(\Delta\text{AUC}=2.33\%\). On the right: PET images of pre- and post-treatment. (For interpretation of the references in this figure legend in colour, the reader is referred to the web version of this article. )other parameters usually used in the nuclear medicine environment. Furthermore, the CSH and AUC parameters showed a good agreement with the patient follow-up after GK treatments. Changes in AUC between baseline and follow-up scans could indicate an increase in necrotic tissue tumour after treatment [22]. In our study, the proposed classification (positive, stable, and negative response) found a good agreement with the patient outcome evaluated by three physicians. In particular, nine patients with a positive response to the treatment showed a reduction in AUC--lower AUC values correspond to greater heterogeneity, which can be associated with an increase in the necrotic tissue, as well as the corresponding MET uptake reduction in the follow-up scans. Conversely, an increase in heterogeneity (positive \(\Delta\)AUC) can indicate a negative response to therapy. As a result, AUC represents a potential clinical index for an early assessment of the treatment response. In fact, functional changes are faster to identify the therapy response than anatomical imaging (CT or MRI). However, the current clinical methodology in nuclear medicine departments is limited to visual assessment or uptake value measurements, such as SUV\({}_{\text{max}}\). Our preliminary results suggest that the proposed parameters could provide better discriminating power for the use of PET imaging in radiotherapy or chemotherapy. These parameters may be incorporated into the planning process to modify patient management.