Stress-testing cross-cancer generalizability of 3D nnU-Net for PET-CT tumor segmentation: multi-cohort evaluation with novel oesophageal and lung cancer datasets

Abstract: Robust generalization is essential for deploying deep learning based tumor segmentation in clinical PET-CT workflows, where anatomical sites, scanners, and patient populations vary widely. This study presents the first cross cancer evaluation of nnU-Net on PET-CT, introducing two novel, expert-annotated whole-body datasets. 279 patients with oesophageal cancer (Australian cohort) and 54 with lung cancer (Indian cohort). These cohorts complement the public AutoPET dataset and enable systematic stress-testing of cross domain performance. We trained and tested 3D nnUNet models under three paradigms. Target only (oesophageal), public only (AutoPET), and combined training. For the tested sets, the oesophageal only model achieved the best in-domain accuracy (mean DSC, 57.8) but failed on external Indian lung cohort (mean DSC less than 3.4), indicating severe overfitting. The public only model generalized more broadly (mean DSC, 63.5 on AutoPET, 51.6 on Indian lung cohort) but underperformed in oesophageal Australian cohort (mean DSC, 26.7). The combined approach provided the most balanced results (mean DSC, lung (52.9), oesophageal (40.7), AutoPET (60.9)), reducing boundary errors and improving robustness across all cohorts. These findings demonstrate that dataset diversity, particularly multi demographic, multi center and multi cancer integration, outweighs architectural novelty as the key driver of robust generalization. This work presents the demography based cross cancer deep learning segmentation evaluation and highlights dataset diversity, rather than model complexity, as the foundation for clinically robust segmentation.