54 - Prospects for Clinical Trials of Metastasis Inhibitors

Summary

TARGETS FOR METASTASIS SUPPRESSION

The process of metastasis has been carefully delineated in recent decades and includes intravasation, survival in the circulation, and arrest in a distant organ; extravasation, survival, and growth after extravasation; and persistence of growth. Although an enormous amount of research has examined the early steps of the metastatic process, it seems unlikely that the earliest steps are amenable to therapeutic intervention. In general, distant metastasis has occurred in the majority of human cancers prior to detection of the primary tumor. In some tumors (e.g., pancreatic cancer) overt metastatic disease is common at diagnosis, whereas in other cancers (e.g., breast and colorectal cancers) micrometastatic disease is present at the time of diagnosis. In either situation, circulating tumor cells have lodged in a distant site long before a patient meets a physician.

Where in the metastatic process will the therapeutic line be drawn? Certainly this will occur somewhere following intravasation and spread through the circulation, and quite possibly following organ arrest (depending on whether tumor dormancy occurs at this point or at a subsequent point, as discussed later). Regardless, metastasis suppression strategies posited solely on interruption of the earliest steps of the metastatic process are unlikely to prove successful in most cases.

There are possible exceptions to the above rule that might render treatment of the early portions of the metastatic process valuable.