Study population
We included 10 patients (6 males and 4 females), all Caucasian with a mean age of 58.4 ± 8.3 years (range: 44–73 years). All patients had a proven head and neck squamous cell carcinoma, with one patient (#5) having two synchronous tumors (1 HNSCC and 1 dedifferentiated carcinoma) (Table 1). Histologic grading showed only 2 patients with poorly differentiated tumor, 4 were well differentiated, and 5 had a moderate differentiation. Finally, one patient (#5) had distant metastasis (2 lung lesions).
PET/CT imaging
PET/CT images were acquired 71 ± 14 minutes (range: 56–90 minutes) after administration of 216 ± 79 MBq (range: 208–250 MBq) 68Ga-NODAGA-RGD. For 18F-FDG, images were acquired 70 ± 11.5 minutes (range: 63–93 minutes) after injection of 3.5 MBq/kg (range: 185-291 MBq). The mean time elapsed since 18F-FDG and 68Ga-NODAGA-RGD PET/CT scans was 2.5 ±1.8 days (range: 1–7 days). Both radiopharmaceuticals were well-tolerated, and no radiopharmaceutical-related adverse effect was observed. The mean time elapsed since biopsy and PET/CT imaging was 17.5 ± 5.3 days (range: 14–24 days)
68Ga-NODAGA-RGD distribution
68Ga-NODAGA-RGD in comparison to 18F-FDG PET/CT images demonstrated different whole-body distributions in all the ten patients. Figure 2 displays body tracers’ distribution of four selected patients. Compared to 18F-FDG images, 68Ga-NODAGA-RGD images demonstrated significantly higher uptake in the spleen and in the kidneys, while the uptake was lower in the brain, the parotid glands, the mediastinum, the myocardium, the lung, the liver, the psoas muscle and the bone (all p<0.037, Figure 3). Similar uptake were measured in the thyroid gland, the gut and the bladder (all p>0.1).
Non-tumoral positive uptake regions were seen in several patients for both tracers, notably due to inflammatory diseases. The majority of them were seen in patients #1, #4, #5 and #6 and were analyzed as glenohumeral joint inflammation proven by clinical data. In patients #1, #2 and #6, stomatitis was proven by mouth and throat examination.
Analysis in the primary tumors
All primary tumours were visually detectable with both tracers (Table 2). Distribution of the tracers within the tumors was different as shown on the axial PET/CT fusion (Figure 1). Compared to magnetic resonance images for tumour delineation, we noticed that 18F-FDG uptake was mostly homogenous inside the tumors. 68Ga-NODAGA-RGD PET showed heterogenous uptake within the tumors. In patients #8 (Figure 4) for instance, moderate uptakes were seen mostly in the periphery of the tumor. Necrotic areas did not display significant uptake for both tracers (Figure 5).
Tumor uptake was significantly higher with 18F-FDG than with 68Ga-NODAGA-RGD (SUVmax 14.0 ± 6.1 g/mL versus 3.9 ± 1.1 g/mL, p=0.0017; SUVmean (8.2 ± 3.1 g/mL versus 2.0 ± 0.8 g/mL, p=0.0017) as was the tumor-to-background ratio (Table 2). One patient showed very low 68Ga-NODAGA-RGD activity (patient #9). A linear positive correlation between the 18F-FDG and the 68Ga-NODAGA-RGD SUVmean was found (Spearman’s rho=0.89, p=0.0068), but not for SUVmax values (Spearman’s rho=0.39, p=0.38). There was no statistically significant relation between age and tracers’ uptake (p= 0.5). As seen in Table 2, “tracer avid tumor volume” was larger with 68Ga-NODAGA-RGD PET/CT with a volume around 30% higher for 68Ga-NODAGA-RGD (Figure 6), but this difference did not reach statistical significance (p=0.085) in comparison to 18F-FDG PET/CT. There was no significant correlation between the uptake volumes of the two tracers (Spearman’s rho= 0.038, p<0.05).
Analysis in the lymph nodes and metastases
All lymph nodes and distant metastases were seen with both tracers. In some cases, such as in patients #9 and #10, 68Ga-NODAGA-RGD uptake was however very low, with a target-to-background ratio <2. The size of the lymph node was measured in short axis (8.5 ± 2.7 mm, range: 4–15 mm), and there was no significant correlation between lymph node size and uptake (p> 0.05). Tracer avid tumor volume was always higher with the 68Ga-NODAGA-RGD PET in the lymph nodes, as seen with in the primary tumors.
Metastatic spread of the disease was seen only in patient #5, with bilateral lung metastases. Lower SUVmax was reported with the 68Ga-NODAGA-RGD PET (7.7 g/mL versus 11.9 g/mL), and higher tracer avid tumor volume (2.8 mL versus 0.8 mL). No statistical analysis of metastatic disease was performed because of the paucity of lesions.
Effect of tumor grade, p16 and HPV status
Both radiotracers’ uptakes did not correlate with tumor grade (p≥0.17). P16 and HPV immunostaining showed a good association between the p16 and HPV tests (p<0.05). Five histopathological analyses were HPV and p16 positive and six were negative. Mean SUVmax values of p16 and HPV positive cases were 16.4 ± 6.9 g/mL with 18F-FDG and 3.8 ± 1.0 g/mL with 68Ga-NODAGA-RGD. Mean SUVmax values of p16 and HPV negative cases were respectively of 9.8 ± 1.7 g/mL with 18F-FDG and 4.1 ± 1.2 g/mL with 68Ga-NODAGA-RGD. No significant difference in both tracers’ uptake was found regarding HPV or p16 protein expression (p=0.22) (Table 4).