In this study, motion-compensated PET/CT revealed no clear clinical benefit compared to 3D PET/CT imaging in oesophageal cancer patients. SUVmax of the primary tumour and lymph nodes was similar between 3D and motion-compensated PET/CT. The MTV2.5 and MTV50% were also similar on both scans for the complete group. In a subgroup of patients (SUVmax of the primary tumour of ≤ 8), large differences of the MTV50% were observed between 3D and motion-compensated PET/CT, probably caused by uptake around a SUV of 4 in inflammatory tissue surrounding the tumour, with the result that minor differences in SUVmax could show large impact on the MTV50%. In addition, threshold-based and endoscopic-based tumour lengths were poorly correlated. Furthermore, the motion-compensated technique did not improve the detection rate of lymph node metastases.
Prior studies on 4D PET/CT in oesophageal cancer focused on the primary tumour volumes only. Guo et al. evaluated the clinical target volumes (CTV) and planning target volumes (PTV) based on 3D CT, 4D CT and 3D PET/CT. Volumes generated with 3D PET with 4D CT were significantly larger than those generated with 3D CT or 4D CT. Direct comparison of 3D PET/CT with 4D PET/CT was, however, not performed. Wang et al. determined GTV volumes on the average 4D PET/CT with auto-contouring methods using eight different thresholds and compared these PET-derived GTVs with a CT-derived GTVs. SUV ≥ 2.5 and SUV ≥ 20% volumes correlated best with tumour length on CT. However, 4D PET/CT was not compared with 3D PET/CT. Scarsbrook et al. compared PTVs on 3D PET/4D CT with 4D PET/CT in 15 oesophageal cancer patients. Volumes on both scans were similar, but overlap analysis demonstrated a median Dice similarity coefficient of 0.88 between both scans, leading to chance of under-coverage. However, the lack of pathology confirmation in this study obviates the clinical interpretation when this part of the volume is excluded from the PTV.
To our knowledge, the presented study is the first study in which the influence of motion-compensated PET/CT on the detection rate of pathological lymph nodes in oesophageal cancer was studied. Unfortunately, motion-compensation did not improve the lymph node detection rate. PET/CT is superior to CT in the detection of distant metastases. However, for the identification of regional lymph node metastases, the sensitivity of PET/CT is insufficient[9, 22]. Moreover, the location of suspicious lymph nodes may influence radiation target volumes and/or choice of surgical approach. Suspicious nodes are included in the radiation target volumes, but larger radiation volumes increase the chance of toxicity[23, 24]. Postoperative complications increase with an extended mediastinal lymph node dissection; a possible long-term benefit should thus be carefully weighed against the risk of a more complicated postoperative course. Preferably, suspicious nodes are cytologically confirmed by EUS-FNA.
In this study, the additional value of motion-compensated PET/CT for the metabolic characterisation of oesophageal cancer was limited. There are several possible explanations for this finding. Firstly, the amplitude of the tumour motion was relatively small; on average 6.0 mm in craniocaudal direction. Zhao et al. described an average oesophageal tumour motion of 8.7 mm in craniocaudal direction using 4D CT. The modest motion amplitude in our study might be explained by the 1 hour resting phase prior to PET/CT acquisition, which is not applicable in the abovementioned CT studies, resulting in more relaxed patients with a more superficial breathing pattern. Kruis et al. investigated the influence of motion amplitude on 4D PET/CT in lung tumours and liver metastases. For targets with a CC motion of less than 5 mm the benefit of motion-compensated PET/CT was limited, while a clear effect was seen with amplitudes of more than 10 mm. This effect was not observed in our study, possibly since only six patients had a peak-to-peak amplitude of > 10 mm.
Secondly, the identification of the borders of the oesophageal tumour on PET/CT imaging may also be difficult. Oesophageal tumours frequently show submucosal spread along the oesophagus and proximal stomach, which might complicate demarcation of the tumour boundaries. Also, oesophagitis and gastritis can give an increased metabolic signal and are often seen in oesophageal cancer patients, limiting differentiation of tumour from inflammation. In patients with tumours with relatively low FDG avidity, this can be even more difficult. These factors hamper demarcation of the tumour, even if the blurring due to the respiratory signal has been compensated for. In this study, the craniocaudal extension of MTVs showed large differences with the tumour length as determined during endoscopy.
And lastly, the accuracy of threshold-based delineation is not only influenced by object motion, but also by other factors, such as metabolic activity of the tumour, homogeneity of uptake, voxel size and signal-to-noise ratio. In this study, we only investigated the influence of object motion.
The threshold-based volumes in this study showed low agreement with tumour length on endoscopy. Currently, semi-quantitative PET analyses are increasingly investigated in oesophageal cancer[29, 30]. Threshold-based volumes are proposed for delineation purposes and SUVmax or metabolic changes are proposed for response assessment or as prognostic factors. However, current segmentation methods show shortcomings. Advanced image segmentation algorithms are emerging that can cope with such challenges. Also, different methodologies for segmentation or combined thresholds can contribute to the robustness of semi-quantitative volumes. However, most of these new segmentation methods have not yet been validated and the most reliable and robust delineation method remains to be found.
The limitations of our study are the relative low motion amplitude of both tumour and lymph nodes during PET/CT acquisition, prohibiting proper analysis of motion-compensated PET/CT in patients with larger amplitude motion. Furthermore, cytological confirmation of lymph node involvement was only available for a limited number of patients and pathological assessment of the actual pre-treatment tumour length was not possible due to neoadjuvant chemoradiotherapy or a non-surgical approach. Despite these limitations, the prospective study design with a relatively large patient sample contributes to current available literature.
In the future, the impact of PET-based measurements may even increase further. In the prospective dose-escalation phase I/II study of Yu et al., definitive chemoradiotherapy was given with an escalated simultaneous integrated boost to the volume of ≥ 50% SUVmax. Encouraging local control rates and acceptable toxicity were seen. Unfortunately, the PET scan technique and segmentation algorithm were not described in the manuscript. For interpretation and implementation of results of studies using PET-volume guided treatment, uniform segmentation methods and PET technique are necessary.