ESTRO 37 Abstract book

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ESTRO 37

OC-0268 FAZA PET hypoxia as a marker of loco- regional recurrence in HNSCC? Results from the DAHANCA 24 trial M. Saksø 1 , L. Mortensen 2 , H. Primdahl 2 , J. Johansen 3 , J. Kallehauge 4 , C. Hansen 5 , J. Overgaard 1 1 Aarhus University Hospital, Dept. of Experimental Clinical Oncology, Aarhus, Denmark 2 Aarhus University Hospital, Dept. of Oncology, Aarhus, Denmark 3 Odense University Hospital, Dept. of Oncology, Odense, Denmark 4 Aarhus University Hospital, Dept. of Medical Physics, Aarhus, Denmark 5 Odense University Hospital, Laboratory of Radiation Physics, Odense, Denmark Purpose or Objective Hypoxia in head and neck squamous cell carcinoma (HNSCC) is an important risk factor when assessing clinical outcome after primary chemo-radiation (RCT). We hypothesized that the hypoxic sub-volumes are areas of the tumor with special resistance to radiation. The volumes can be visualized using molecular imaging with PET/CT and 18 F-fluoroazomycin arabinoside (FAZA). If the hypothesis is true, these areas would be predominant sites of treatment failure. The purpose of this study was 1) to report on cumulative incidence of loco-regional failures within 5 years after primary RCT in a prospective cohort and 2) to characterize the site of failure in terms of presence of hypoxia visualized by pre-treatment FAZA PET/CT. Material and Methods From 2009-2011, 40 patients with squamous cell carcinoma of the larynx, pharynx and oral cavity planned for primary RCT were included in the prospective phase II trial, DAHANCA 24. All were imaged with a static 2h-post injection FAZA PET/CT prior to treatment. The DAHANCA database were used for updates on clinical outcomes. Any recurrence was documented by both histology and imaging with MRI, PET/CT or a combination. The attenuation CT of the FAZA scan was merged with recurrence imaging and the spatial information were visually compared. Results Patients were mostly in advanced clinical stages (80% in stages III-IV) and most had oropharyngeal primaries (60%). Twenty-five of 40 patients had FAZA-avid, hypoxic tumors before treatment (63%). In total, 38 patients completed treatment as prescribed. With a median follow-up of 4.9 years, 9 loco-regional recurrences were observed, and 8 of these in patients with initially hypoxic tumors (cum. incidence of 32% and 8% respectively, p=0.04). Human Papilloma Virus-driven disease (expressed as p16-positive disease) was seen for 17 patients (43%), but in patients with recurrence for only 3 tumors, who were all hypoxic. Eight patients had recurrence imaging sufficient for co- registration with the FAZA PET/CT. Seven of these had hypoxic primary tumors, but for less than half of these patients, the recurrence was in or overlapping with the hypoxic sub-volumes. One patient had a T-site failure cranially to the initially FAZA-avid, hypoxic sub-volume. For 3 patients, failure occurred in newly developed lymph nodes not initially part of primary tumor volume (two recurrences in the elective field and one out-of-field). Conclusion The risk of loco-regional treatment failure is high for patients with hypoxic tumors as assessed by FAZA PET/CT before treatment. Hypoxia imaging with FAZA has potential for selection of patients for dose escalation, but not likely for dose painting guidance, as the pattern of failure does not convincingly support the hypothesis of the hypoxic sub-volume being the major origin of recurrent disease.

Results Relative to the aorta, tumors and muscle reached equilibrium at 7.3±4.1 and 71±24 min, respectively. There was differential [ 18 F]FAZA distribution and/ or clearance in muscle compared to aorta, highlighting the importance of reference region standardization. Improved and stable tumor-to-reference region contrast was seen at 2-2.5 h, compared to 1.5-2 h pi . TMR max was significantly higher than TAR max at 2-2.5 h pi ( p =0.0331). HVs and HFs based on the 3 thresholds were significantly different with fixed 1.2 > image-derived > fixed 1.4 ( figure 2A ). An image-derived threshold adapts to the image quality by quantifying the variability of [ 18 F]FAZA uptake in normoxic reference tissue, compared to fixed >1.2 threshold which overestimates hypoxia. HVs and HFs based on an image-derived and fixed >1.2 thresholds showed good repeatability, compared to fixed >1.4 threshold which exhibited moderate to poor scan-scan repeatability ( figure 2B ). Shortening [ 18 F]FAZA PET acquisition duration (from 30 min to 20 min and 10 min) lowers the sensitivity to detect hypoxic voxels. Non- specific pimonidazole immunostaining was seen in tumor stroma ( figure 2C ), inflammatory cells ( figure 2D ) and necrotic regions ( figure 2E) . All examined tumour specimens demonstrated positive pimonidazole immunostaining, with different pimonidazole immunostaining patterns in adenocarcinoma compared to squamous cell carcinoma (SCC). There was concordance in the hypoxic status classification between [ 18 F]FAZA PET and pimonidazole immunostaining in all 4 SCC patients but not in the 2 adenocarcinoma patients with tissue data.

Conclusion Important new [ 18 F]FAZA PET validation data are presented that are necessary to permit optimal application of this modality to derive potential NSCLC hypoxia biomarkers.