Predictive value of fluorodeoxyglucose (FDG) PET/CT parameters
The ability to identify some factors to predict or assess treatment response at an early stage after the start of treatment would be of great value. Extensive research shows that metabolic-related parameters, such as standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor have the potential to become valuable predictors and prognostic biomarkers in EC patients.49–52
Kato et al assessed the potential value of metabolic-related parameters in predicting the response to treatment.53 The SUVmean before CRT in the non-CR group and the CR group were 10.2 and 4.9, respectively. The SUVmean after treatment in the two groups was 3.7 and 1.4, respectively. The changes in SUV of the CR patients were significantly lower than those of the non-CR patients (p<0.05). The author concluded that the SUVmean before CRT of the primary tumor has the potential to become a valuable predictor for response (p<0.05). Similarly, Atsumi et al performed a study to assess the efficacy of metabolic-related parameters for the prediction of response in DCRT for EC.54 The results showed that the SUVmax values for the CR arm were higher than that in the non-CR arm, and all 18 patients in the low-SUV group had a CR. The data suggest that the SUVmax was a valuable predictor for response. However, Javeri et al evaluated the initial standardized unit value of FDGPET and its association with the degree of pathological response after CRT.55 Their work revealed that SUV higher than the median (10.1) was associated with a better pathological response (p=0.06). Similarly, Levine et al and Rizk et al also reported a high initial SUVmax was associated with better response.56,57 These conflicting results could be potentially attributed to differences in patient populations, tumor histology types, grouping criteria, as well as treatment, but they might also indicate that predictive value of SUV values are unreliable.
Recently, some studies have considered that SUVmax, which reflects only a single point in the tumor, may not always be representative of the whole tumor.58 In contrast to SUVmax, volumetric parameters such as MTV and TLG represent the dual characteristics of tumor volume and the degree of tumor uptakes FDG.59 Therefore, volumetric parameters based on 18F-FDG PET/CT have been proposed as a more valuable biomarker for predicting survival or response to CRT than SUVmax in patients with EC. Roedl et al evaluated the value of volumetric parameters in predicting response to CRT in patients with EC. They found that a decrease in the metabolic tumor diameter between pre- and posttreatment was the single best predictor of tumor response and survival outcome.60 In another study, Jayachandran et al evaluated the value of MTV on PET scanning in predicting response to CRT in patients with EC. They found that the MTV2.5 and TLG2.5 were valuable markers for predicting the tumor response.61 Another study also showed that the changes in MTV and TLG between pre- and posttreatment were more precise for predicting pathological response than ΔSUVmax.62 However, they showed that none of these parameters were very accurate in predicting a pCR and that the volumetric parameters had a marginally higher accuracy than SUVmax in predicting treatment response to CRT. Overall, available data suggest that these metabolic parameters may be useful as predictors of treatment response, while the ability to predict accurately is still limited.
Predictive value of CT perfusion parameters
CT perfusion is a promising imaging tool in oncology; it can visualize changes in the tumor’s vascular physiology and introduces elements of functional diagnostics in morphological imaging.63,64 Respecting this fact could be potentially useful in monitoring the response of the tumor to the CRT.
Stefanovic et al evaluated the value of the CT perfusion parameters in predicting response to CRT.65 In their study, 40 patients with SCC were reevaluated after CRT. The CT perfusion parameter values after the CRT were significantly correlated with tumor regression grade. These results showed that CT perfusion imaging can predict the response to CRT. Hansen et al also reported that CT perfusion parameters could be an early predictor of treatment response to CRT in EC.66
To further investigate the utility of each perfusion parameter for predicting histopathologic response in EC following chemoradiation, a great deal of research was performed. In the study performed by Hayano et al, they found that higher baseline blood flow (BF), higher baseline blood volume (BV) and low mean transit time (MTT) correlated significantly with a good response.67 In another EC study, Makari et al examined changes in tumor perfusion before and after chemoradiation in ESCC.68 The results showed that responders had a significantly higher baseline BF and a significantly shorter baseline MTT than non-responders, while BV did not in ESCC. Similar to the findings already mentioned, Djuric-Stefanovic et al questioned whether the CT perfusion parameters could be useful to predict the pCR of EC to CRT.69 The results showed that BFpost-CRT, BVpost-CRT, and permeability surfacepost-CRT were significantly lower and MTTpost-CRT was significantly higher in the pCR group. The investigators concluded that CT perfusion parameters enable accurate prediction of pCR of EC to CRT, which could be useful in improving patient selection for further treatment.
In conclusion, both FDG PET parameters and CT perfusion parameters could be a good predictor for treatment response. Such predictive factors could help to identify the subgroups that are more likely to benefit from radiation dose escalation.
Individualized radiation dose escalation based on decrease of tumor FDG uptake
The available data indicate that a decrease in tumor FDG uptake correlates with OS and pathological response for patients with EC.70 Cuenca et al performed a study showing that metabolic response during CRT for locally advanced EC has a great prognostic value.71 Using a 50% decrease in SUVmax as a cut-off, the 2–year OS in the good metabolic responders and poor responders was 62% and 27%, respectively (p=0.016). Similarly, Javeri et al declared that the higher the decrease of tumor FDG uptake after treatment, the better the survival of EC patients.72 Metabolic response using PET/CT is a surrogate for histopathological response in predicting sensitivity to treatments of patients with EC.73Evaluating the decrease in tumor FDG uptake could help to identify good responders to CRT. Thus, individualized radiation dose escalation based on decrease in tumor FDG uptake after standard radiation of 50.4 Gy could be feasible. According to the European Organization for Research and Treatment of Cancer criteria, metabolic response on FDGPET was divided into the following four types: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease, and progressive metabolic disease.74,75 CMR was defined as complete resolution of 18F-FDG uptake within the tumor volume so that it was indistinguishable from surrounding normal tissue. On the basis of our conjecture, patients with CMR may not need to receive dose escalation after the standard radiation of 50.4 Gy, which may reduce the treatment-related toxicities. Patients with PMR may benefit from dose escalation after a conventional radiation dose of 50.4 Gy. Of those with minor residual tumor after planned radiation, limited dose escalation would achieve CMR without increasing toxicities. These patients could benefit the most from dose escalation. For those with major residual tumor and no metabolic response after planned radiation, limited dose escalation may not change the persistence of local disease because of tumor resistance to CRT. Above all, it is necessary to determine the feasibility of individualized radiation dose escalation after planned chemoradiation based on the decrease in tumor FDG uptake.
Individualized radiation dose escalation based on flow-metabolic phenotypes
It has been reported that malignant tumors differ in terms of BF perfusion and glucose metabolism phenotype.76–78 For example, there are: 1) high-perfusion high-metabolism tumors; 2) low-perfusion low-metabolism tumors; 3) high-perfusion low-metabolism tumors; and 4) low-perfusion high-metabolism tumors (Figure 1). A combined assessment of the flow-metabolic phenotype of EC using integrated 18F-FDG PET/perfusion CT may be of additional value in assessing the response to therapy as well as in identifying the patients who might be more likely to benefit from radiation dose escalation. Several studies have investigated the relationship between 18F-FDG PET and perfusion CT, demonstrating that the balance between tumor vascularity and glucose metabolism offers massive information regarding tumor treatment response.76–78 Tumors with matched high perfusion and glucose metabolism show a constitutive up-regulation of angiogenesis and metabolism; tumors with matched low perfusion and glucose metabolism likely reflect necrosis; whereas tumors that present with low perfusion and high glucose metabolism show an adaptation to hypoxia.79 Thus, integrated 18F–FDG PET/perfusion CT makes it possible to distinguish different phenotypes; this may be useful in guiding individualized dose escalation based on functional imaging in patients with EC.