Radiolabeled cetuximab: dose optimization for epidermal growth factor receptor imaging in a head-and-neck squamous cell carcinoma model.

Noninvasive imaging of the epidermal growth factor receptor (EGFR) in head-and-neck squamous cell carcinoma could be of value to select patients for EGFR-targeted therapy. We assessed dose optimization of (111) Indium-DTPA-cetuximab ((111) In-cetuximab) for EGFR imaging in a head-and-neck squamous cell carcinoma xenograft model. (111) In-cetuximab slowly internalized into FaDu cells in vitro, amounting to 1.0 × 10(4) molecules cetuximab per cell after 24 hr (15.8% of added activity). In nude mice with subcutaneous FaDu xenograft tumors, a protein dose escalation study with (111) In-cetuximab showed highest specific accumulation in tumors at protein doses between 1 and 30 μg per mouse (mean tumor uptake 33.1 ± 3.1%ID/g, 3 days postinjection (p.i.)). The biodistribution of (111) In-cetuximab and (125) I-cetuximab was determined at 1, 3 and 7 days p.i. at optimal protein dose. Tumor uptake was favorable for (111) In-cetuximab compared to (125) I-cetuximab. With pixel-by-pixel analysis, good correlations were found between intratumoral distribution of (111) In-cetuximab as determined by autoradiography and EGFR expression in the same tumor sections as determined immunohistochemically (mean r = 0.74 ± 0.14; all correlations p < 0.0001). Micro Single Photon Emission Computed Tomography (MicroSPECT) scans clearly visualized FaDu tumors from 1 day p.i. onward and tumor-to-background contrast increased until 7 days p.i. (tumor-to-liver ratios 0.58 ± 0.24, 3.42 ± 0.66, 8.99 ± 4.66 and 16.33 ± 11.56, at day 0, day 1, day 3 and day 7 p.i., respectively). Our study suggests that, at optimal cetuximab imaging dose, (111) In-cetuximab can be used for visualization of EGFR expression in head-and-neck squamous cell carcinoma using SPECT.

Hoeben BA ，Molkenboer-Kuenen JD ，Oyen WJ ，Peeters WJ ，Kaanders JH ，Bussink J ，Boerman OC ... -  《-》

Imaging of epidermal growth factor receptor expression in head and neck cancer with SPECT/CT and 111In-labeled cetuximab-F(ab')2.

van Dijk LK ，Hoeben BA ，Kaanders JH ，Franssen GM ，Boerman OC ，Bussink J ... -  《-》

177Lu-labeled antibodies for EGFR-targeted SPECT/CT imaging and radioimmunotherapy in a preclinical head and neck carcinoma model.

Liu Z ，Ma T ，Liu H ，Jin Z ，Sun X ，Zhao H ，Shi J ，Jia B ，Li F ，Wang F ... -  《-》

Early response monitoring with 18F-FDG PET and cetuximab-F(ab')2-SPECT after radiotherapy of human head and neck squamous cell carcinomas in a mouse model.

Only a subset of patients with head and neck squamous cell carcinomas (HNSCCs) benefit from radiotherapy and concurrent epidermal growth factor receptor (EGFR) inhibitor therapy with cetuximab, indicating the need for patient selection. The aim of this study was to visualize the change in systemically accessible EGFR with (111)In-cetuximab-F(ab')2 SPECT before and after radiotherapy, while simultaneously evaluating (18)F-FDG PET uptake. Mice with HNSCC xenografts, cetuximab-sensitive SCCNij202 and cetuximab-resistant SCCNij167, were imaged with SPECT/CT using (111)In-cetuximab-F(ab')2 as a tracer, directly followed by PET imaging with (18)F-FDG. Scans were acquired 7 d before radiotherapy (10 Gy) and 1, 7, and 14 d after treatment. Intratumoral localization of (111)In-cetuximab-F(ab')(2) was evaluated by autoradiography and histologic markers evaluated by immunofluorescence staining in the same tumor sections. Growth of irradiated SCCNij202 and SCCNij167 tumors was significantly delayed, compared with controls (P < 0.05). No changes in uptake of (18)F-FDG were observed in either of the xenografts after radiotherapy. SPECT images of tumor-bearing mice showed a significant increase in uptake of (111)In-cetuximab-F(ab')(2) in the SCCNij202 tumors after irradiation (tumor-to-liver ratio, 4.3 ± 1.1 vs. 10.5 ± 3.3, 7 d before and 14 d after treatment, respectively, P < 0.01) but not in SCCNij167 tumors. Immunohistochemical EGFR staining showed a translocation of the EGFR from the cytoplasm to the cell membrane in irradiated SCCNij202 xenografts. Intratumoral distribution of (111)In-cetuximab-F(ab')(2) as determined by autoradiography correlated well with the distribution of EGFR as determined immunohistochemically (r = 0.85; range, 0.69-0.95). EGFR accessibility can be visualized with (111)In-cetuximab-F(ab')(2). (111)In-cetuximab-F(ab')(2) uptake increased after irradiation only in cetuximab-sensitive SCCNij202 xenografts, implying that the tracer can be used to measure irradiation-induced changes of EGFR expression and can monitor the compensatory response of tumors to radiotherapy.

van Dijk LK ，Boerman OC ，Franssen GM ，Lok J ，Kaanders JH ，Bussink J ... -  《-》

111In-cetuximab-F(ab')2 SPECT and 18F-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 with radiotherapy and the epidermal growth factor receptor (EGFR) inhibitor cetuximab shows an improved response in a subgroup of patients. The aim of this study was to noninvasively 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 head and neck squamous cell carcinomas xenografts, SCCNij202 or SCCNij185, were imaged with SPECT/CT using (111)In-cetuximab-F(ab')2 (5 μg, 28 ± 6.1 MBq, 24 h after injection), followed by PET imaging with (18)F-FDG (9.4 ± 2.9 MBq, 1 h after injection). Scans were acquired on mice 10 d before treatment with either single-dose irradiation (10 Gy), cetuximab alone, or cetuximab-plus-irradiation combined or on untreated control mice. Scans were repeated 18 d after treatment. Tumor growth was monitored up to 120 d 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, scan 2 - scan 1) 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 with the first scan (P < 0.005 and <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. (18)F-FDG PET tumor uptake (maximum standardized uptake value, scan 2 - scan 1) correlated with tumor response for SCCNij202 (P < 0.01) but not for SCCNij185 (P = 0.66). EGFR fractions were significantly different: 0.9 ± 0.1 (SCCNij202) and 0.5 ± 0.1 (SCCNij185) (P < 0.001). The EGFR fraction was significantly lower for irradiated SCCNij202 tumors than for controls (P < 0.005). (111)In-cetuximab-F(ab')2 predicted and monitored the effects of EGFR inhibition 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. Thus, the additional value of the (111)In-cetuximab-F(ab')2 tracer is emphasized and the tracer can aid in evaluating future treatments with EGFR-targeted therapies.

van Dijk LK ，Boerman OC ，Franssen GM ，Kaanders JH ，Bussink J ... -  《-》