Chemokine Receptor-4 Targeted PET/CT Imaging with 68Ga-Pentixafor in Head and Neck Cancer-A Comparison with 18F-FDG and CXCR4 Immunohistochemistry

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) is common, and its incidence is increasing, particularly in HIV-infected individuals who present with more aggressive disease. Despite aggressive treatment, the prognosis remains poor because of resistance to chemoradiation therapy. So far, studies report very low [⁶⁸Ga]Ga-Pentixafor avidity in HNSCC. This study investigated the diagnostic performance of CXCR4-directed imaging of carcinoma of the oral cavity, oropharynx, and nasopharynx with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine ligand [⁶⁸Ga]Ga-Pentixafor and explored its ability to quantify CXCR4 expression in vivo.

Materials and methods: In this prospective cross-sectional study, twenty-three (23) patients aged 52.9 ± 10.4 (19.6), 17 males and 6 females with primarily diagnosed (n = 17) or pre-treated (n = 6) SCC of the oral cavity (OCSCC, n = 11), oropharynx (OPSCC, n = 9), nasopharynx (NPSCC, n = 2) and unknown primary (n = 1) underwent imaging with [⁶⁸Ga]Ga-Pentixafor-PET/CT. In 16/23 patients 2-[18F]fluoro-2-deoxy-D-glucose ([¹⁸F]F-FDG) served as a standard reference. All lesions were visually rated using a 5-point Likert scale. For both tracers, maximum standardized uptake values (SUVmax) and the total lesion uptake (TLU) were recorded and compared using the Wilcox-signed rank test. In addition, the tumor-to-background ratios were derived using the liver (TLR), spleen (TSR), and posterior cervical muscles (TMR) as background. The relationships between the SUVs of the two tracers were assessed using the Spearman correlation. CXCR4 immunohistochemistry (IHC) staining was correlated with ⁶⁸Ga-Pentixafor-PET/CT in 21/23 patients.

Results: Ninety-one percent (21/23) of tumors were visually detected on [⁶⁸Ga]Ga-Pentixafor; however, [⁶⁸Ga]Ga-Pentixafor was less intense compared with [¹⁸F]F-FDG-PET. Quantitative analysis showed higher [¹⁸F]F-FDG SUVmax in comparison with [⁶⁸Ga]Ga-Pentixafor (16 ± 6.7 vs. 5.8 ± 2.6 g/mL, p = 0.011) and SUVmean (9.3 ± 4.1 vs. 3± 1.6 g/mL, p < 0.001) and TBR 4.9 ± 2.3 vs. 2.36 ± 1.4 p = 0.014. Nasopharyngeal cancer demonstrated more intense tracer accumulation than oropharyngeal and oral cavity malignancies. CXCR4 IHC staining was positive in 15/21 patients, and there was a statistically significant correlation between IHC staining and [⁶⁸Ga]Ga-Pentixafor SUVmean r = 0.5 p = 0.027, and performance status r = 0.83 p = 0.0104.

Conclusions: In conclusion, although [⁶⁸Ga]Ga-Pentixafor cannot replace [¹⁸F]F-FDG as a diagnostic tool because of its lower avidity, the correlation between CXCR4 targeted ⁶⁸Ga-Pentixafor PET imaging and CXCR4 IHC staining indicates the potential of ⁶⁸Ga-Pentixafor as an effective tool for selecting patients who may benefit from therapies targeting CXCR4. In addition, [⁶⁸Ga]Ga-Pentixafor has no physiological brown fat uptake, which often obscures cervical lesions on [¹⁸F]F-FDG PET/CT imaging.

Keywords: CXCR4; HIV; PET; Pentixafor; head and neck carcinoma.

Figure 1

Flowchart displaying the composition of enrolled patients.

Figure 2

Example of a moderate CXCR4-positive, high FDG-positive patient. Display of [¹⁸F]F-FDG-PET/CT (a–d) and ⁶⁸Ga]Pentixafor-PET (e–h) (interval between both scans, 14 days) in a 60-year-old male patient with oral cavity SCC (patient #6). [⁶⁸Ga]Pentixafor-PET demonstrates less intense tracer accumulation at the site of primary SUVmax 4.84 (b) compared with 18.36 on [¹⁸F]F-FDG (f), the left cervical node metastasis also showed more intense uptake on [¹⁸F]F-FDG (c), SUVmax 14.41 versus 5.29 on [⁶⁸Ga]Ga-Pentixafor (g).

Figure 3

Example of a CXCR4-positive, FDG-positive patient. Display of maximum intensity projection (MIP), axial and coronal slices of both [¹⁸F]F-FDG PET/CT (a–d) and [⁶⁸Ga] Ga-Pentixafor-PET CT (e–h) (interval between both scans, 3 days) in a 49-year-old female with oropharyngeal SCC (Patient #18). [¹⁸F]F-FDG PET/CT demonstrates intense uptake in the primary lesion (d) SUVmax 33.06 and right cervical lymph node (c) SUVmax 23.35. [⁶⁸Ga] Ga-Pentixafor-PET also demonstrates intense tracer accumulation at the primary site (h) SUVmax 10.94 and cervical nodes 8.33 (g), respectively. CXCR4 IHC stain was strongly positive in 90% of the cells.

Figure 4

Example of a high CXCR4-positive, high FDG-positive patient. Display of maximum intensity projections of [¹⁸F]F-FDG (a) and [⁶⁸Ga]Ga-Pentixafor (d) and sagittal images of both [¹⁸F]F-FDG-PET/CT (b) and [⁶⁸Ga]Ga-Pentixafor-PET/CT (e) (interval between both scans, 14 days) in a 46-year-old HIV-positive female patient oropharyngeal SCC (patient #13). [⁶⁸Ga]Ga-Pentixafor-PET (f) demonstrates high inhomogeneous tracer accumulation at the site of primary SUVmax 11.73 compared with 19.46 on [¹⁸F]F-FDG (c). Note the brown fat paraspinal uptake on FDG (a) is not present on [⁶⁸Ga]Ga-Pentixafor (d). CXCR4 IHC (20× magnification) demonstrated membranous and cytoplasmic staining in 60% of the cells.

Figure 5

Example of a high FDG, low Pentixafor in mediastinal nodes. Display of maximum intensity projections of [¹⁸F]F-FDG (d) and [⁶⁸Ga]Ga-Pentixafor (h) and axial and sagittal images of both [¹⁸F]F-FDG-PET/CT (a,b) and [⁶⁸Ga]Ga-Pentixafor-PET/CT (e,f) (interval between both scans, 16 days) in a 46-year-old HIV-negative female patient oropharyngeal SCC (patient #9). [⁶⁸Ga]Ga-Pentixafor-PET demonstrates mild-moderate inhomogenous tracer accumulation at the site of primary SUVmax 2.63 (a) compared with 16.93 (e) on [¹⁸F]F-FDG. Multiple foci of intense uptake are seen in inflammatory the mediastinal lymph nodes on [¹⁸F]F-FDG (c), these appear less intense on [⁶⁸Ga]Ga-Pentixafor-PET (g). Notably, the spleen demonstrates higher uptake on [⁶⁸Ga]Ga-Pentixafor (h) compared to [¹⁸F]F-FDG-PET/CT (d).

Figure 6

Kaplan–Meier curves show no statistically significant difference between survival in the patients who had positive IHC stains for CXCR4 and those who had negative stains.

Figure 7

Kaplan–Meier curves show no statistically significant difference between survival in the HIV-infected patients compared with the HIV-uninfected patients with HN cancer.

Figure 8

Survival time for patients with ¹⁸F-FDG SUVmax < 16.93 vs. >= 16.93 showing poorer survival in patients with FDG SUVmax >= 16.93; however, this did not reach statistical significance Pr > chi2 = 0.1670.