Over the past 20 years, researchers at Tel Aviv University have been investigating whether-and how-surgical removal of a primary cancerous tumor (for example, colorectal, pancreatic, ovarian or breast tumors) may in some cases increase the risk of metastatic spread that becomes clinically evident months or even years after a successful surgery. Accumulating evidence suggests that surgery can, under certain conditions, accelerate and amplify metastatic processes. This occurs, among other mechanisms, through stress and inflammatory responses of the patient’s body, which are triggered by the surgery itself and by its physiological and psychological effects.

 

Because surgical removal of the primary tumor is essential for saving the lives of cancer patients, it is critically important to reduce or prevent these adverse surgery-related effects in order to improve surgical efficacy and increase patients’ chances of long-term recovery from cancer.

 

Based on findings from our own research and from studies conducted by other investigators, using both animal models and human clinical studies, it has become clear that:

1. The short time window surrounding surgery has a disproportionately large impact in shaping metastatic processes that may manifested years later.

2. Even modest changes in risk factors for metastasis during this critical perioperative period can shift the balance toward anti-metastatic conditions and prevent long-term cancer recurrence. In other words, during the perioperative window the body has a greater capacity to halt or eliminate metastatic processes. Supporting the body at this critical stage can therefore make it relatively easier to prevent future metastatic disease. If the body fails at this stage, combating metastases at a later phase becomes far more difficult.

3. We have identified specific stress and inflammation related responses to surgery that underlie the acceleration of metastatic processes. In particular, (a) heightened sympathetic nervous system activation and, (b) excessive production of prostaglandins via the COX-2 enzyme, beyond what is necessary for surgical recovery, act synergistically to promote metastasis. Numerous researchers from leading institutions worldwide have independently reported findings that support these conclusions.

Based on these insights, we developed a drug-based intervention using existing, safe, and low-cost medications (Deralin and Etopan, known generically as propranolol and etodolac) that block harmful stress and inflammation related effects. In animal studies across six different cancer types, we demonstrated that administering this drug combination during the perioperative period prevents metastasis and improves survival following removal of the primary tumor. Following these successes, we transitioned to treating cancer patients using the same drug combination.

Recently, we completed two clinical trials in Israel: one in breast cancer patients and one in colorectal cancer patients. In both studies, molecular analyses of the surgically removed tumors revealed that tumors from patients who received the drug treatment exhibited a reduced metastatic potential, mirroring findings previously observed in animal studies.

Importantly, the drug treatment may also slow the progression of existing metastatic foci, even independently of surgery. Furthermore, in the completed colorectal cancer study, patients who received the drug treatment showed a significantly lower cancer recurrence rate five years after surgery (2 out of 16 patients), compared with the placebo group (9 out of 18 patients). These findings demonstrate that the drug intervention may indeed prevent metastatic recurrence.

​