Cetuximab-F(ab')2-SPECT and FDG-PET for prediction and response monitoring of combined modality treatment of human head and neck carcinomas in a mouse model

Treatment of head and neck squamous cell carcinomas (HNSCC) with radiotherapy and EGFR-inhibitor cetuximab shows an improved response in a subgroup of patients. The aim of this study was to non-invasively monitor treatment response by visualizing systemically accessible EGFR with (111)In-cetuximab-F(ab')2 while simultaneously evaluating tumor metabolism with (18)F-FDG PET during combined modality treatment.Eighty mice with patient-derived HNSCC xenografts, SCCNij202 or SCCNij185, were imaged with SPECT/CT using (111)In-cetuximab-F(ab')2 (5 µg, 28 ± 6.1 MBq, 24 h p.i.) followed by PET imaging with (18)F-FDG (9.4 ± 2.9 MBq, 1 h p.i.). Scans were acquired 10 days prior to treatment with either single-dose 10 Gy, cetuximab alone, cetuximab + 10 Gy combined or untreated controls. Scans were repeated 18 days post treatment. Tumor growth was monitored up to 120 days after treatment. EGFR expression was evaluated immunohistochemically.SCCNij202 responded to combined treatment (P < 0.01) and cetuximab treatment alone (P < 0.05), but not to irradiation alone (P = 0.13). SCCNij185 responded to combined treatment (P < 0.05) and irradiation (P < 0.05), but not to cetuximab treatment alone (P = 0.34). (111)In-cetuximab-F(ab')2 uptake (tumor-to-liver ratio, scan2-scan1) predicted response to therapy. A positive response to treatment significantly correlated with a reduced tracer uptake in the tumor in the second SPECT scan compared to the first scan (P < 0.005, P < 0.05 for SCCNij202 and SCCNij185, respectively). Resistance to therapy was characterized by a significantly increased (111)In-cetuximab-F(ab')2 tumor uptake; tumor-to-liver ratio was 2.2 ± 0.6 to 3.5 ± 1.2, P < 0.01 for (irradiated) SCCNij202 and 1.4 ± 0.4 to 2.0 ± 0.3, P < 0.05 for (cetuximab-treated) SCCNij185, respectively. FDG-PET tumor uptake (SUVmax, scan2-scan1) correlated with tumor response for SCCNij202 (P < 0.01) but not for SCCNij185 (P = 0.66). EGFR fractions (fEGFR) were significantly different: 0.9 ± 0.1 (SCCNij202) and 0.5 ± 0.1 (SCCNij185) (P < 0.001). fEGFR was significantly lower for irradiated SCCNij202 tumors, compared to controls (P < 0.005).(111)In-cetuximab-F(ab')2 predicted and monitored the effects of EGFR-inhibition and/or irradiation during treatment in both head and neck carcinoma models investigated, whereas (18)F-FDG-PET only correlated with tumor response in the SCCNij202 model. This emphasizes the additional value of the (111)In-cetuximab-F(ab')2 tracer and can aid in evaluating future treatments with EGFR-targeted therapies