title: 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.
abstract: 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  (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.
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands; and Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands laura.vandijk@radboudumc.nl.
authors.forename: Laura K
authors.initials: LK
authors.lastname: van Dijk
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Gerben M
authors.initials: GM
authors.lastname: Franssen
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands; and.
authors.forename: Johannes H A M
authors.initials: JH
authors.lastname: Kaanders
authors.affiliation: Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands; and.
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000378:metabolism; D000068818:Cetuximab; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007128:Immunoglobulin Fragments / Q000737:chemistry*; D007150:Immunohistochemistry; D007205:Indium Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D007128:Immunoglobulin Fragments; D007205:Indium Radioisotopes; D019788:Fluorodeoxyglucose F18; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: HNSCC; PET; SPECT; cetuximab; radiotherapy