Hypoxia in relationship to tumor volume using hypoxia PET-imaging in head & neck cancer – A scoping review

BACKGROUND: Hypoxia and large tumor volumes are negative prognostic factors for patients with head and neck squamous cell carcinoma (HNSCC) treated with radiation therapy (RT). PET-scanning with specific hypoxia-tracers (hypoxia-PET) can be used to non-invasively assess hypoxic tumor volume. Primary tumor volume is readily available for patients undergoing RT. However, the relationship between hypoxic volume and primary tumor volume is yet an open question. The current study investigates the hypotheses that larger tumors contain both a larger hypoxic volume and a higher hypoxic fraction. METHODS: PubMed and Embase were systematically searched to identify articles fulfilling the predefined criteria. Individual tumor data (primary tumor volume and hypoxic volume/fraction) was extracted. Relationship between hypoxic volume and primary tumor volume was investigated by linear regression. The correlation between hypoxic fraction and log(2)(primary tumor volume) was determined for each cohort and in a pooled analysis individual regression slopes and coefficients of determination (R(2)) were weighted according to cohort size. RESULTS: 21 relevant articles were identified and individual data from 367 patients was extracted, out of which 323 patients from 17 studies had quantifiable volumes of interest. A correlation between primary tumor volume and PET-determined hypoxic volume was found (P <.001, R(2) = 0.46). Larger tumors had a significantly higher fraction of hypoxia compared with smaller tumors (P<.01). The weighted analysis of all studies revealed that for each doubling of the tumor volume, the hypoxic fraction increased by four percentage points. CONCLUSION: This study shows correlations between primary tumor volume and hypoxic volume as well as primary tumor volume and the hypoxic fraction in patients with HNSCC. The findings suggest that not only do large tumors contain more cancer cells, they also have a higher proportion of potentially radioresistant hypoxic cells. This knowledge can be important when individualizing RT.