Primary and secondary metastatic dissemination: multiple routes to cancer-related death

Abstract

Metastatic disease accounts for approximately 80% of cancer-related deaths, typically manifesting as single-organ failure mainly through abdominal, cardiovascular, neurological, or respiratory complications. Despite treating thousands of cancer patients daily worldwide, our understanding of organ-specific metastatic dissemination routes, tissue destruction mechanisms and reasons for organ failures remains limited. As cancer-directed therapies advance, maintaining organ function has emerged as a critical therapeutic goal of care. To develop more effective treatment strategies, a comprehensive understanding of the pathophysiology is essential, particularly regarding secondary and subsequent metastatic waves that lead to extensive macro-metastases and organ failure. Critical distinction between primary metastatic spread and secondary intra-organ dissemination is crucial. In the era of precision oncology, elucidating organ-specific destruction processes and the pathophysiology of metastatic waves is fundamental for advancing patient care. To highlight the emerging goal of care of maintaining organ function, we aligned the metastatic biology, clinical stages, goals of care and therapeutic indications: the Bio Therapeutic Goals of Cancer Care Model.

Keywords: Bio Therapeutic Goals of Cancer Care Model; CNS; Cancer-directed therapy; Metastasis; Metastatic dissemination; Primary dissemination; Secondary dissemination.

Fig. 1

Peritoneal metastasis. Overview of local complications of peritoneal metastasis including wrapping of the intestine, intestinal wall destruction, obstipation, malignant ascites, epithelial barrier break down, vessel invasion, organ infiltration, and vascular walling

Fig. 2

Overview of potential life-threatening scenarios and respective organ or compartment failures

Fig. 3

Overview of vascular and alternative non-vascular dissemination routes. Vascular dissemination routes include haematogenous dissemination and lymphatic dissemination. Alternative non-vascular dissemination routes include iatrogenic dissemination, intra-cavity dissemination, intraluminal dissemination, dissemination per continuitatem, perineural dissemination, and perivascular dissemination

Fig. 4

Overview of dissemination routes into or via the CNS compartment. Dissemination routes include transmigration of the blood CSF barrier via the choroid plexus, perineural dissemination along cranial nerve II (optical nerve), perineural dissemination bilateral along spinal nerves, perivascular dissemination via emissary vessels to CSF space, and secondary dissemination to CSF space and the meninges. CSF: cerebrospinal fluid, PND: perineural dissemination

Fig. 5

Bio Therapeutic Goals of Cancer Care Model. Interplay of (A) metastatic biology and stages, (B) goals of care, and (C) therapeutic indications. EoL: end of life, OMD: oligo metastatic disease