Macrovascular infiltration and spikes in circulating tumor cells in cancer patients approaching end of life

End-of-life neoplastic events related to carcinoma lethality are poorly characterized. With the purpose of exploring biological events in cancer patients nearing death, we conducted an observational, prospective, case-control study enrolling 21 patients with solid tumors and 10 patients without known malignancy, complemented by a retrospective validation cohort of 1,250 cancer patients. In our prospective cohort, we observed remarkable spikes in circulating tumor cell (CTC) counts immediately before death (P < 0.0001), as well as pathological evidence of macrovascular infiltration and large-vessel occlusion obtained through rapid autopsy. In the validation cohort, radiological evidence of macrovascular infiltration emerged as the strongest predictor of poor survival – independent of clinical metastasis – in treatment-homogenous patients with colorectal, lung, ovarian, hepatocellular, or pancreatic cancer (hazard ratio range: 4.0 - 22.4). These findings suggest that spikes in CTC formation and consequent macrovascular failure could be pivotal end-of-life events associated with cancer lethality, providing a rationale for future clinical trials aimed at curbing tumor infiltration into large vessels.