In Vivo Quantification of Hypoxic and Metabolic Status of NSCLC Tumors Using [18F]HX4 and [18F]FDG-PET/CT Imaging

Abstract

Objective Increased tumor metabolism and hypoxia are related to poor prognosis in solid tumors, including non-small cell lung cancer (NSCLC). PET imaging is a non-invasive technique which is frequently used to visualize and quantify tumor metabolism and hypoxia. The aim of this study was to perform an extensive comparison of tumor metabolism using FDG PET and hypoxia using HX4 PET imaging. Materials/Methods FDG- and HX4-PET/CT images of 25 NSCLC patients were co-registered. At a global tumor-level, HX4 and FDG parameters were extracted from the gross-tumor-volume. The HX4-high fraction and high volume were defined using a tumor-to-blood ratio>1.4. For FDG-high fraction and high volume a SUV>50% of SUVmax was used. We evaluated the spatial correlation between HX4 and FDG uptake within the tumor, to quantify the (mis)match between volumes with a high FDG and high HX4 uptake. Results At a tumor-level, significant correlations were observed between FDG and HX4 parameters. For the primary GTV, the HX4-high fraction was three times smaller compared to the FDG-high fraction. In 53% of the primary lesions, less than 1cm3 of the HX4-high-volume was outside the FDG-high volume; for 37% this volume was 1.9–12cm3. Remarkably, a distinct uptake pattern was observed in 11%, with large hypoxic volumes localized outside the FDG-high volume. Conclusion Hypoxic tumor volumes are smaller than metabolic active volumes. Approximately half of the lesions showed a good spatial correlation between the PET tracers. In the other cases, a (partial)mismatch was observed. The addition of HX4-PET imaging has the potential to individualize patient treatment.

TH-302 in Combination with Radiotherapy Enhances the Therapeutic Outcome and Is Associated with Pretreatment [18F]HX4 Hypoxia PET Imaging

“…18 F]HX4 PET imaging (11,13), and IHC of pimonidazole adducts (9). Although [ 18 F]HX4 hypoxia PET imaging represents the whole tumor in a noninvasive, reproducible, three-dimensional manner, IHC stainings can, in addition to hypoxia, extract more tumor microenvironmental information from the same tumor section.…”

“…18 F]HX4 is a reliable tool for the noninvasive detection of hypoxic tumor regions (9)(10)(11). Because TH-302, like tirapazamine, is expected to have only a therapeutic effect when hypoxic regions are present in the tumor (12), [ 18 F]HX4 PET imaging may function as a useful predictive biomarker.…”

Validation of functional imaging as a biomarker for radiation treatment response

“…Currently, HX4 is being studied in clinical trials in non-small-cell lung cancer (NSCLC). 13,14 Furthermore, an ongoing clinical study investigates HX4-PET in patients with head and neck squamous cell carcinoma (HNSCC) and compares HX4-PET uptake with 18 F-FDG PET uptake before and during (chemo)radiotherapy (ClinicalTrials.gov identifier: NCT01347281). [15][16][17] In recent years radiotracer-based molecular imaging with PET, mainly using the glucose analogue 18 F-FDG, has been shown to improve accuracy in the diagnosis and staging of various tumour types.…”

“…FMISO was the first radiotracer proposed for detecting hypoxia with PET 50 and has been evaluated clinically. 13,14,33 Intertumoral pre-treatment uptake of hypoxia PET tracers has been found in several studies to be prognostic for response to radiotherapy in patients with head and neck cancer. 12,13,21,23,29,32,34,40,51,52 It is also well recognized that uptake of hypoxia PET tracers in individual patients shows pronounced heterogeneity, even though it is yet unclear whether this observation has prognostic value for achieving local control in specific tumour subvolumes.…”

“…13,14,33 Intertumoral pre-treatment uptake of hypoxia PET tracers has been found in several studies to be prognostic for response to radiotherapy in patients with head and neck cancer. 12,13,21,23,29,32,34,40,51,52 It is also well recognized that uptake of hypoxia PET tracers in individual patients shows pronounced heterogeneity, even though it is yet unclear whether this observation has prognostic value for achieving local control in specific tumour subvolumes. 21 Far more difficult than to study the impact of hypoxia on outcome in different patients is to investigate also whether information on intratumoral heterogeneity within an individual tumour can be used for the selection of optimal treatment such as combination of radiotherapy with hypoxia modifiers or biologically individualized radiation treatment such as "dose painting".…”