There is a pattern in breast cancer relapse data that oncology has known about for decades and rarely explains to patients. When you plot recurrences over time, they do not fall on a smooth curve. There is an early spike, a wave of relapses that clusters in the months right after surgery, and then a second, lower peak years later. That first wave is too early and too synchronized to be random.
Michael Retsky and Patrice Forget argued the uncomfortable explanation. The early peak is not just cancer being cancer. Part of it may be created by the surgery itself.
https://doi.org/10.3332/ecancer.2020.1050
This is not an argument against surgery. Surgery removes the tumor. It works, and for most patients it should not be skipped. It is important to recognize, however, that local tumor control does not always translate into improved overall survival. In select settings, such as metastatic kidney cancer in the CARMENA trial, removing the primary tumor did not improve survival compared with systemic therapy alone. For most localized solid tumors, however, surgery remains the cornerstone of curative treatment. I will come back to that in a future post. The point here is different. The act of cutting sets off a physiological storm that, for a brief window, tilts the body in favor of any cancer cells left behind. Not because surgeons do anything wrong. Because this is what a body does when you wound it. And that window is one we can actually do something about.
A while back, I wrote that cancer is as much a disease of the tissue environment as of the cell, that the terrain a tumor sits in can push it toward growth or hold it in check, linked below for your viewing.
The perioperative window is that idea compressed. Surgery briefly turns the terrain tumor-permissive. Unlike chronic stress or inflammation, this shift has a start date on the calendar, which is exactly what makes it something we can act on.
What actually happens when you cut
The moment surgery begins, the body floods with catecholamines and prostaglandins. Adrenaline, noradrenaline, and the inflammatory signaling that drives wound healing. These are the same molecules that let you survive an injury. They also happen to be growth signals for cancer.
https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2026.1796434/full
Three things follow:
Surgical stress suppresses natural killer cell function, the exact immune cells whose job is to find and destroy circulating tumor cells, and that suppression lands right when it matters most.
The inflammatory surge, IL-6, CRP, and the rest, feeds any residual disease and can wake micrometastases out of dormancy.
Catecholamines acting on beta-adrenergic receptors push tumor cells toward an invasive, mobile state and stimulate the new blood vessels a growing metastasis needs.
We can even watch part of this happen in real time now. Circulating tumor cell counts measurably spike during and immediately after an operation. Removing the tumor physically sheds cells into the bloodstream. So you have a window of maybe two weeks where the immune system is down, the inflammatory signaling is up, more tumor cells are in circulation, and whatever escaped is getting a growth signal. That is the biology behind the early relapse wave.
The elegant part
If catecholamines and prostaglandins are the problem, we already have cheap, decades-old, well-understood drugs that block both. Propranolol, a beta-blocker, and a COX-2 inhibitor to blunt the prostaglandin arm.
In a randomized phase II trial in 2017, thirty-eight women with early-stage breast cancer received eleven days of perioperative propranolol plus etodolac (NSAID), starting five days before surgery. The drugs were well tolerated, with side effects no different from placebo. Then they looked at the excised tumors and the blood.
The treated tumors showed reduced epithelial-to-mesenchymal transition, the shift that lets a cell become mobile and invasive. The prometastatic and proinflammatory transcription factors driving spread were turned down. Ki-67, a marker of proliferation, dropped. The surgical spike in IL-6 and CRP was blunted. The immune profile shifted in a favorable direction. In eleven days, with two generic drugs, they changed the molecular behavior of the tumor and the host in exactly the direction you would want.
This is biomarker data, not survival data, but it is human data, it is randomized, and the mechanism underneath it is not controversial.
And it is not only breast cancer. The same perioperative propranolol and etodolac approach was tested in colorectal surgery, and at eight years the treated patients had fewer recurrences, two of fifteen versus nine of eighteen. Tiny numbers, but a hard endpoint from a randomized design. Angiosarcoma, a vascular tumor driven through the same beta-adrenergic signaling, sometimes regresses on propranolol outright. Retrospective data in breast and melanoma link beta-blocker use around diagnosis to lower recurrence, and there are roughly twenty active trials across tumor types.
Other levers in the same window
Once you see the window, other cheap tools line up on the same pathways.
Aspirin strips the platelet cloak that shields circulating tumor cells from immune attack, on top of blocking prostaglandins. The signal is strongest in PIK3CA-mutated colorectal cancer, and the Add-Aspirin trial, running since 2015, is testing it across tumor types. Cimetidine, an old H2 blocker, lowers E-selectin on blood vessel walls so shed tumor cells lose the docking sites they use to exit circulation and seed. Omega-3 fatty acids feed the resolvin pathway, the body’s active off-switch for the same IL-6 and prostaglandin surge. None of these replaces treatment. Each aims at the same residual-disease biology the window exposes.
What we do and do not know
We do not yet have a large randomized trial proving that perioperative beta-blockade lowers recurrence or extends survival. The strong human evidence is at the level of biomarkers and mechanism. The clinical outcome signals we do have come from weaker designs. A 2018 prospective cohort out of Florence by Vincenzo De Giorgi gave off-label propranolol to patients with thicker melanomas and reported roughly an eighty percent reduction in recurrence risk. That number is striking, and it is also a cohort study where patients chose whether to take the drug, which invites bias.
The good news is we may finally be getting a way to measure this per patient. Tumor-informed circulating tumor DNA tests can now detect molecular residual disease after surgery, below the resolution of any scan, and a positive result is one of the strongest predictors of relapse we have. That gives us a real endpoint for whether anything done in the window actually clears residual disease, instead of waiting years to find out. A bit more on that from the archives below.
Why you have never heard of this
No company owns propranolol or generic anti-inflammatories. There is no financial engine to run the large trials or market the idea. The surgical window is short and nobody’s specialty fully owns it, so it falls between the surgeon, the oncologist, and the anesthesiologist and gets picked up by none of them. This is not a conspiracy. It is what happens to a good idea with no sponsor.
I believe the perioperative window is one of the most underused opportunities in oncology. Low cost, low risk, biologically sound, and begging to be used.
What you can actually do
This is not a DIY therapy. Propranolol has real contraindications, including asthma, certain heart conditions, and low heart rate or blood pressure, and it has to be dosed and supervised by a physician. So the move here is a conversation, not a prescription you get on the internet.
If you have a cancer surgery coming up, here is where I would push.
Ask the specific question: “Would you be open to prescribing perioperative propranolol with a COX-2 inhibitor like celecoxib or etodolac, on the eleven-day schedule from the 2017 Ben-Eliyahu trial, starting five days before surgery?” Bring the trial printed, and stay open to their answer.
Expect to be told no, and know why. The likely answer is “there is no large survival trial,” which is true. Decide in advance whether an eleven-day course of two generic drugs, with a placebo-level side effect profile and solid mechanism, is worth it to you without that trial.
Talk about your anesthesia plan. Ask about an opioid-sparing plan and regional or neuraxial anesthesia where the surgery allows. Opioids and the surgical stress response both suppress natural killer cells, the exact defense you want intact that week. The recurrence data here is mixed, but it is worth the conversation.
Get molecular residual disease tracking, by name. Ask for a tumor-informed ctDNA test such as Signatera, drawn a few weeks after surgery and then serially every three months. A positive result is one of the strongest relapse predictors we have, and it turns “wait and scan” into something you can actually track.
Do not stop the right drugs. If you already take a beta-blocker, aspirin, or metformin, tell your surgical team and do not stop them around surgery without guidance. Each one touches the same catecholamine, platelet, and metabolic pathways this window runs on.
Take matters into your own hands. In the two weeks around surgery, protect sleep, keep blood sugar stable, get fresh air and cut stress inputs where you can. These feed the same catecholamine and inflammatory surge as the incision. It is free, it is safe, and almost no one tells you it matters.
Assume you are the only one connecting the dots. The surgeon, oncologist, and anesthesiologist each own a piece of this window and none of them own the whole thing. Bring me or your integrative physician into the planning before the date is set, not after. This window is measured in days, and it does not reopen.
Ksenia Malarkey, ND is a naturopathic physician specializing in integrative oncology, hormones, and metabolic health.
She provides medical care for Washington residents and offers global health coaching.
To schedule a free 15-minute consult, visit drkseniamalarkey.com
What happens to the body when the host has no time to prepare?
I am a 69-year-old white female in relatively good health and not on any prescription drugs who had a robotic cholecystectomy in March. I am one of the unfortunate ones that was diagnosed with postcholecystectomy syndrome post-op. Ten days ago, I had a sudden onset of excruciating pain in my lower abdomen and thigh and went to the ER. I ended up having an obturator hernia with a piece of small bowel trapped inside and underwent emergency surgery to repair the hernia and relieve the blockage. Every day feels like a slog. I am off narcotics and just taking Tylenol. I walk twice a day in the sun. I’m eating four meals a day to try to gain some weight. I’m sleeping about 6 to 7 hours a night. I pray and meditate. I still feel like crap. Are there any other suggestions for the postoperative period other than what I’ve been doing or is it just tincture of time as one of my favorite intensivists used to say?
Excellent perspective! As a physician-scientist, I think the perioperative period is one of the most underappreciated windows in cancer care. While surgery is often the cornerstone of curative treatment for solid tumors, the days before and after an operation also represent a period of profound physiological change that can influence recovery and, potentially, long-term outcomes.
The body’s response to surgery involves coordinated immune activation, inflammation, wound healing, metabolic adaptation, and neuroendocrine signaling. Optimizing factors such as nutritional status, physical conditioning (“prehabilitation”), glycemic control, sleep, and postoperative mobilization can improve resilience and reduce complications. Increasingly, research is exploring how this perioperative environment may also influence tumor biology, although many questions remain about which interventions meaningfully affect recurrence and survival.
I also appreciate the growing emphasis on preparing patients rather than simply operating on them. Surgery shouldn’t be viewed as a single event but as one phase within a continuum of care. Helping patients enter the operating room in the best possible physiological condition may be just as important as the technical success of the procedure itself.
The future of surgical oncology will likely become increasingly personalized, integrating molecular tumor profiling, perioperative optimization, enhanced recovery protocols, and precision supportive care. It’s an exciting shift from focusing solely on removing the tumor to optimizing the biology of the patient throughout the entire treatment journey.
Thanks again!