Lymphocyte Infiltration Determines the Hypoxia-Dependent Response to Definitive Chemoradiation in Head-and-Neck Cancer - Results from a Prospective Imaging Trial

Head and Neck Cancer

J Nucl Med. 2020 Aug 28:jnumed.120.248633. doi: 10.2967/jnumed.120.248633. Online ahead of print.


Tumor hypoxia in head-and-neck squamous cell carcinoma (HNSCC) leads to an immunosuppressive microenvironment and reduces the response to radiotherapy. In this prospective imaging trial, we investigated potential interactions between functional hypoxia imaging and infiltrating lymphocyte levels as a potential predictor for treatment response in HNSCC patients. Methods: 49 patients receiving definitive chemoradiation for locally advanced HNSCCs underwent pre-therapeutic biopsies and peri-therapeutic hypoxia imaging using Fluorine-18-misonidazole (18F-FMISO) PET at weeks 0, 2 and 5 during chemoradiation. Hematoxylin-eosin and immunohistochemical stainings for tumor-infiltrating lymphocytes, tissue-based hypoxia and microvascular markers were analyzed and correlated with the longitudinal hypoxia dynamics and patient outcomes. Results: High levels of tumor-infiltrating total lymphocytes correlated with superior loco-regional control (LRC) (HR=0.279, P = 0.011) and progression-free survival (PFS) (HR=0.276, P = 0.006). Similarly, early resolution of 18F-FMISO PET-detected tumor hypoxia quantified by 18F-FMISO dynamics between weeks 0 and 2 of chemoradiation was associated with improved LRC (HR=0.321, P = 0.015) and PFS (HR=0.402, P = 0.043). Outcomes in the favorable early hypoxia resolution subgroup significantly depended on infiltrating lymphocyte counts with patients showing both early hypoxia response and high lymphocyte infiltration levels exhibiting significantly improved LRC (HR=0.259, P = 0.036) and PFS (HR=0.242, P = 0.017) compared to patients with early hypoxia response but low lymphocyte counts. These patients exhibited comparable oncological results to patients with no hypoxia response within the first 2 weeks of chemoradiation. Conclusion: This analysis established a clinical hypoxia-immune score that predicted treatment responses and outcomes in HNSCC patients undergoing chemoradiation which may help to devise novel concepts for biology-driven personalization of chemoradiation.