Harnessing the Perioperative Period to Improve Long-term Cancer Outcomes

The short perioperative period, spanning several days pre- and postsurgery, is now believed to have a nonproportionally large impact on long-term cancer outcomes (1,2). Numerous physiological responses to the newly discovered cancer and to surgical resection trigger pro-metastatic processes that can affect minimal residual disease (MRD; single tumor cells/micrometastases). MRD can potentially seed into new organs, escape from dormancy, and/or accelerate its growth, eventually becoming life threatening. Underlying processes for such surgery-induced deleterious effects include 1) immune suppression, 2) excessive shedding/spreading of tumor cells, 3) systemic release of growth factors (3), and 4) numerous direct pro-metastatic effects of stress and inflammatory mediators on MRD, increasing its proliferation, migration, and invasion capacity, as well as MRD release of pro-angiogenic and pro-growth factors (4,5). These multiple processes occur simultaneously during the perioperative period and act synergistically to facilitate metastatic progression. On the other hand, the removal of the primary tumor diminishes several ongoing metastasis-driving processes (5). Thus, a new and delicate balance between pro- and antimetastatic processes is created perioperatively, which may determine whether MRD will erupt postoperatively or will regress to dormancy—two opposing processes that are each self-perpetuating and bear long-term critical ramifications (5). Therefore, the perioperative period should be exploited therapeutically to achieve an antimetastatic balance, before pro-metastatic processes prevail irreversibly (1).

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