Development and Validation of Diagnostic Interpretation Criteria for Evaluation of F-18 Fluoromisonidazole Hypoxia PET/CT – Inter-Reader Reliability and Accuracy

Abstract

<h3>Purpose/Objective(s)</h3> F-18 Fluoromisonidazole (FMISO) is a robust imaging biomarker for tumor hypoxia. Hypoxia limits effective cancer treatment, specifically radiotherapy in head and neck cancers. We have completed and have ongoing trials using hypoxia imaging to guide radiation dose de-escalation. To ensure wide applicability, we sought to develop and validate standardized qualitative and quantitative criteria to accurately and reliably interpret clinical FMISO PET/CT images. <h3>Materials/Methods</h3> All HPV+ oropharyngeal cancer patients who had FMISO PET/CT imaging before and about 2 weeks into chemoradiation therapy and pre-treatment F-18 FDG PET/CT were included. 4 independent nuclear medicine (NM) physicians with varying clinical experience of 1, 3, 5, and 15 years with no FMISO experience interpreted images. Training and reference interpretations were performed by a 5^th NM physician with 30 years of clinical and 15 years of FMISO experience. Suspicious cervical lymph nodes (LN) > 1 cm in short axis with abnormal FDG avidity on FDG PET/CT were categorized as positive or negative for FMISO uptake. A LN was considered positive if it demonstrated SUVmax visually greater than floor of mouth (FOM). FMISO SUVmax of the LN and FOM were obtained using a 3D VOI. The training and validation process consisted of: (1) initial instruction; (2) practice interpretation; (3) one on one re-training on contentious group reads; (4) final group training; (5) validation interpretation of new scans. Qualitative, visual comparison of FMISO uptake in LN to FOM, and quantitative, ratio of FMISO SUVmax of LN to FOM, were analyzed. The Fleiss κ coefficient (κ) was calculated to measure inter-reader agreement. <h3>Results</h3> 192 FMISO scans were included. Qualitative criteria mean sensitivity and specificity (SE/SP) after initial instruction were 0.773 and 0.809. κ was 0.338. Mean SE/SP after additional training were 0.976 and 0.869. κ was 0.864 [95%CI: 0.782 to 0.944]. For the quantitative criteria, ROC curve analysis was used to estimate the best threshold by maximizing the Youden index, which was determined to be SUVmax LN/SUVmax FOM > 1.2. Quantitative criteria mean SE/SP after additional training were 0.896 and 0.953. κ was 0.859 (95%CI: 0.761 to 0.944). The quantitative criteria alone demonstrated a lower sensitivity than the qualitative, 0.896 vs. 0.976. Therefore, we suggest using a hybrid method with quantitative criteria as a guide with the ultimate decision based on qualitative assessment to minimize the number of patients with false negatives and subsequent undertreatment. <h3>Conclusion</h3> The hybrid qualitative/quantitative diagnostic interpretation criteria developed for evaluating FMISO PET/CT in combination with dedicated training has substantial inter-reader agreement and excellent diagnostic performance. This suggests that multi-institutional studies that employ FMISO PET for patient stratification in prospective trials are feasible and can be implemented.