Hypoxic tumor cells are resistant to radiotherapy and various chemotherapeutic agents. The pretherapeutic assessment of intratumoral hypoxia may allow selection of patients for intensified treatment regimens. Carbonic anhydrase IX (CAIX) is an endogenous hypoxia-related protein involved in pH regulation and is upregulated in many tumor types. Radionuclide imaging using a monoclonal antibody against CAIX, such as cG250, may allow noninvasive PET of hypoxia in these tumor types. The aims of this study were to investigate whether 89 Zr-labeled cG250-F(ab9) 2 allowed visualization of tumor hypoxia using small-animal PET and whether the tracer showed spatial correlation to the microscopic distribution of CAIX-expressing cells in a human head and neck xenograft tumor model. Methods: Athymic mice with subcutaneous human head and neck carcinoma xenografts (SCCNij3) were imaged with small-animal PET after injection of 89 Zr-cG250-F(ab9) 2 . PET images were parameterized in terms of standardized uptake values (SUVs). After injection with the nitroimidazole hypoxia marker pimonidazole and the perfusion marker Hoechst 33342, the animals were sacrificed, tumors excised, and CAIX-and pimonidazole-marked hypoxia and blood perfusion were analyzed immunohistochemically. 89 Zr-cG250-F(ab9) 2 tumor uptake was analyzed by ex vivo activity counting and by autoradiography of tumor sections. Results: As early as 4 h after administration, accumulation of 89 Zr-cG250-F(ab9) 2 in the tumor had occurred and tumors were clearly visualized by PET, with reduced uptake by 24 h after injection. Pixel-bypixel analysis showed a significant positive spatial correlation between CAIX expression and 89 Zr-cG250-F(ab9) 2 localization (r 5 0.57-0.74; P , 0.0001). Also, significant correlations were found between pimonidazole staining intensity and 89 ZrcG250-F(ab9) 2 activity concentration, although less strong (r 5 0.46-0.68; P , 0.0001). Tumor maximum SUV correlated significantly with tumor uptake determined ex vivo (r 5 0.93; P 5 0.0067), as did fractions of CAIX and pimonidazole in tumor sections (r 5 0.75; P 5 0.03 and r 5 0.78; P 5 0.02, respectively). Conclusion: 89 Zr-labeled cG250-F(ab9) 2 small-animal PET showed rapid accumulation in a head and neck xenograft tumor model with good correlation to CAIX expression on a microscopic level.
This prospective study used sequential PET with the proliferation tracer 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT) to monitor the early response to treatment of head and neck cancer and evaluated the association between PET parameters and clinical outcome. Methods: Forty-eight patients with head and neck cancer underwent 18 F-FLT PET/CT before and during the second and fourth weeks of radiotherapy or chemoradiotherapy. Mean maximum standardized uptake values for the hottest voxel in the tumor and its 8 surrounding voxels in 1 transversal slice (SUV max (9) ) of the PET scans were calculated, as well as PET-segmented gross tumor volumes using visual delineation (GTV VIS ) and operator-independent methods based on signalto-background ratio (GTV SBR ) and 50% isocontour of the maximum signal intensity (GTV 50% ). PET parameters were evaluated for correlations with outcome. Results: 18 F-FLT uptake decreased significantly between consecutive scans. An SUV max (9) decline $ 45% and a GTV VIS decrease $ median during the first 2 treatment weeks were associated with better 3-y disease-free survival (88% vs. 63%, P 5 0.035, and 91% vs. 65%, P 5 0.037, respectively). A GTV VIS decrease $ median in the fourth treatment week was also associated with better 3-y locoregional control (100% vs. 68%, P 5 0.021). These correlations were most prominent in the subset of patients treated with chemoradiotherapy. Because of low 18 F-FLT uptake levels during treatment, GTV SBR and GTV 50% were unsuccessful in segmenting primary tumor volume. Conclusion: In head and neck cancer, a change in 18 F-FLT uptake early during radiotherapy or chemoradiotherapy is a strong indicator for long-term outcome. 18 F-FLT PET may thus aid in personalized patient management by steering treatment modifications during an early phase of therapy.
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 111Indium‐DTPA‐cetuximab (111In‐cetuximab) for EGFR imaging in a head‐and‐neck squamous cell carcinoma xenograft model. 111In‐cetuximab slowly internalized into FaDu cells in vitro, amounting to 1.0 × 104 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 111In‐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 111In‐cetuximab and 125I‐cetuximab was determined at 1, 3 and 7 days p.i. at optimal protein dose. Tumor uptake was favorable for 111In‐cetuximab compared to 125I‐cetuximab. With pixel‐by‐pixel analysis, good correlations were found between intratumoral distribution of 111In‐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, 111In‐cetuximab can be used for visualization of EGFR expression in head‐and‐neck squamous cell carcinoma using SPECT.
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