Strategies to prevent the promotion of tumor metastasis by surgery and stress: From animal studies to clinical applications.

CS12-03

Although indispensable, surgical procedures for the removal of primary tumors cause marked immunosuppression in cancer patients, and were suggested by animal and human studies to promote tumor progression and metastasis via various mechanisms. To devise prophylactic measures, we conducted studies aiming at identifying specific aspects of surgery contributing to these adverse effects, and specific endocrine and immunological mechanisms mediating them. Additionally, we assessed whether immunostimulation with innocuous doses of a ds-RNA (Poly-IC), with various Th1-type cytokines, and with CpG ODN, could effectively boost cellular immunity or protect it from suppression by stress and surgery, thus reducing postoperative metastasis. As the deleterious effects of surgery are most likely mediated by multiple mechanisms, we aim at devising multimodal strategies to reduce metastasis and improve postoperative survival. To study NK cytotoxicity and host resistance to intravenously inoculated tumor cells, we used two syngeneic tumor lines in F344 rat - the CRNK-16 leukemia, and the MADB106 mammary adenocarcinoma that metastasizes only in the lungs. NK cells, important for controlling metastasis and leukemia, were harvested from the blood and from the lungs' vasculature, counted, and their cytotoxicity assessed against the syngeneic MADB106 and the standard YAC-1 target lines. Our findings to date indicate that the following aspects of surgery could contribute to its adverse effects: a) anesthetic agents - most potently fentanyl and ketamine, less so thiopental and halothane, and propofol not at all; b) severe hypothermia (35-30 ºC); c) tissue damage; and d) perioperative pain and psychological stress. The following treatments attenuated the promotion of metastasis by surgery and/or stress, and usually the suppression of NKA: 1) Sympathetic nerve system blockade or β-adrenoceptor blockade, 2) inhibition of prostaglandin (PG) synthesis, 3) perioperative pain alleviation, 4) spinal block, and 5) minor tranquilizer (diazepam). A selective β-blocker (propranolol) and a COX2 inhibitor (etodolac - a PG synthesis inhibitors) reduced the suppression of NK activity in a synergistic manner and on a per NK cell basis. These drugs can be used perioperatively in cancer patients, as can be various techniques of spinal block. The use of pre-operative immuno-stimulatory approaches was also found effective. Treating rats with repeated low doses of Poly-IC (0.1 mg/kg/day), IL-12 (4 μg/kg/day), or CPG (330 μg/kg/day), improved postoperative/post-stress resistance to MADB106 metastasis and CRNK-16 progression. Importantly, these benefits seemed to be mediated via different immunological mechanisms. While IL-12 caused a marked increase in the numbers of NK cells (e.g., an 8-fold in pulmonary marginating NK cells), it did not protect NK cells from suppression by stress or surgery. Poly I-C, on the other hand, induced a smaller increase in numbers of NK cells, but markedly protected single lung NK cells from suppression by surgery and stress. To optimize the benefits of the different approaches, we devised a regimen based on a combination of IL-12, a selective β-blocker, and a COX2 inhibitor. This regimen increased numbers of NK cells pre-operatively, protected them from suppression by surgery, and completely abrogated the deleterious effects of surgery on resistance to MADB106 metastasis. Retrospective data in cancer patients are consistent with our ability to reduce postoperative metastasis by spinal block, and with the deleterious effects of opiates: A recent publication indicate that, compared to standard opioid analgesia, paravertebral analgesia for breast cancer surgery reduced the risk of recurrence or metastasis approximately four-fold during a 2.5 to 4-year follow-up period (95% CI of estimated hazard ratio is 0.71 - 0.06). Overall, the perioperative period is characterized by increased progression of metastasis, for which immunosuppression seems a critical factor. The above prophylactic measures were devised for potential clinical implementation, and their use in cancer patients could improve long-term survival rates. The use of these approaches would also assess the degree in which postoperative immunosuppression is a risk factor for tumor progression in cancer patients.