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Perioperative beta-blocker plus COX-2 inhibitor to reduce metastasis after surgery

Surgery stress may help hidden cancer cells spread. A five-day course of two cheap old drugs around the operation might block that, and small trials look promising.

Surgical stress releases catecholamines and prostaglandins that suppress anti-tumour immunity and promote metastatic seeding in animal models. Phase 2 trials of propranolol plus etodolac around surgery in breast and colorectal cancer (Ben-Eliyahu and colleagues) showed favourable changes in tumour transcriptomic markers of metastasis and immune suppression, and a small colorectal trial suggested reduced recurrence. Both drugs cost cents. The proposal is a publicly funded, multinational phase 3 in colorectal and breast cancer with disease-free survival as the primary endpoint.

Hypothesis
Perioperative propranolol and etodolac for about five days improve 5-year disease-free survival by an absolute 5 percentage points or more in stage II-III colorectal cancer compared with placebo.
Rationale
The biology is well characterised, the intervention is short, and the perioperative window is a plausible point of vulnerability for micrometastatic disease that no expensive therapy targets.
What would test it
Phase 3 randomised placebo-controlled trial of roughly 1,500 patients in colorectal cancer with DFS primary endpoint and recurrence transcriptomic biomarkers in a sub-study.
Maturity
early clinical
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
6
Bottlenecks it attacks

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