From center to edge: Prognostic implications of spatial metabolic heterogeneity, normalized hotspot-to-centroid and perimeter distance, on PET imaging. A systematic review and meta-analysis.

OBJECTIVE

Tumor heterogeneity remains a major challenge in oncology, influencing prognosis and treatment response. Novel PET-derived spatial radiomic features, including the normalized hotspot-to-centroid (NHOC) and normalized hotspot-to-perimeter (NHOP) distances, aim to quantify intratumoral metabolic heterogeneity and spatial distribution of metabolic activity. These biomarkers may provide biologically interpretable indicators of tumor aggressiveness and patient outcomes. The aim of this study was to systematically evaluate the prognostic and predictive performance of NHOC and NHOP derived from PET imaging across different tumor types.

METHODS

A systematic review and meta-analysis were conducted according to PRISMA guidelines. PubMed/MEDLINE and Google Scholar were searched up to March 2026. Studies evaluating NHOC or NHOP extracted from PET imaging in cancer patients were included. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled using random-effects models.

RESULTS

Ten studies involving 1,496 patients were included. Elevated NHOC was statistically significantly associated with worse OS (HR of 2.313, 95% CI [1.418, 3.775], p = 0.001). Subgroup analysis showed a strong association in lung cancers (2.864, 95% CI [2.018, 4.063], p < 0.001), while results in breast cancer and glioma were inconclusive due to limited data. Decrease in NHOP demonstrated a non-significant trend toward poorer PFS (HR = 2.92, 95% CI: 0.71-11.92). Predictive models based on NHOC showed moderate performance (AUC up to 0.77).

CONCLUSIONS

PET-derived spatial biomarkers, particularly NHOC, show promise as prognostic indicators of tumor aggressiveness and survival outcomes. Larger multicenter studies with standardized imaging protocols are needed to validate their clinical utility.