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Spreading Cancer (Or Just Waking It Up)

If you look at any collection of “common myths about cancer”, you will probably find reassurances about the idea that having cancer surgery might cause the cancer to spread to other parts of the body. I remember coming across this one some years ago being surprised – I’d never heard that one myself, but it was apparently a pretty widespread fear. You could imagine a situation where tumor cells are mechanically detached and could spread, but that’s actually less likely than it might seem, since not all of these cells can actually attach somewhere else and start growing again (although there are special situations where such disturbance, even to the level of taking a biopsy sample, is known to be risky).

What I didn’t know enough about, though, is an effect seen in breast cancer treatment. After surgery, the risk of being diagnosed with metastatic breast cancer peaks about 12 to 18 months later. It’s not a sure thing, fortunately, but it’s definitely a real effect, and one that would certainly lead to people thinking that the surgery had (somehow) spread the cancer around. That’s actually a pretty reasonable hypothesis, given the observations, so that particular “common myth” has something behind it. But how? The same effect is noted in patients who have undergone complete mastectomy, which doesn’t disturb the tumor tissue itself much (or at all). Alternatively, were these actively growing tumors that had spread before the surgery and were just too small to detect? Some have argued for this explanation, and it’s hard to disprove. There’s yet another plausible mechanism: these tumor cells might have had already spread before the surgery, but were somehow not growing, and something happened to change that. What is it about surgery that would allow them to start growing?

This new paper has what may well be the answer. Studying the effects of surgery in mouse models of metastatic cancer, it appears that the post-surgical wound healing response is the culprit. There appears to be an ongoing T-cell response that is holding down these potential metastatic tumors, but it’s disrupted by the inflammation response after surgery. Expressing GFP in murine mammary tumors and then injecting these into other (syngenic) mice caused a T-cell response to the GFP itself, and ultimately the tumors were rejected by the immune system. But surgically wounding these mice triggered an outgrowth of the tumors instead, probably through the actions of inflammatory monocytes (which differentiate into macrophages inside the tumor tissue).

What’s even more interesting is that these effects can be abrogated simply by treating the mice with NSAIDs to damp down the inflammation response. To avoid interactions between the tumor cells and the anti-inflammatory drugs, the procedure was to do the surgical wounding (with and without NSAID treatment with meloxicam) several days before the tumor cells were even injected, with time enough to clear the system out:

Notably, treatment with meloxicam did not appear to impede wound healing in these mice. Seven days after surgical wounding (4 days after the cessation of either meloxicam or saline treatment), D2A1-GFP cells were orthotopically injected contralateral to the wound site. Meloxicam treatment had no effect on tumor growth in the absence of surgical wounding (Fig. 4G, left). In contrast, in wounded groups, tumors in meloxicam-treated mice were significantly smaller than tumors in wounded mice treated with saline (P < 0.05; Fig. 4G, right). Surprisingly, tumors in wounded, meloxicam-treated mice were even smaller than tumors in unwounded, untreated mice.

Interestingly, there had been a retrospective study of breast cancer patients that suggested that treatment with NSAIDs seemed to reduce the metastatic events, but no one was sure if that was a direct mechanistic effect on pre-existing tumors, or on their possible activation. These results, though, suggest that it really is an activation mechanism, and that patients should be treated with NSAIDs in just this way.

We undertook to model a clinical phenomenon that occurs at low frequency and arises only with delayed kinetics in patients. We therefore used hundreds of mice to ensure that we had sufficient statistical power to draw firm conclusions. In considering these conclusions, we do not wish to suggest that tumor resection surgery be avoided because of the potentially negative side effects suggested previously by clinical data and demonstrated here experimentally. Instead, we argue that coupling surgery with short-term anti-inflammatory treatments may substantially improve patient outcomes by mitigating the systemic consequences of surgical breast cancer resection. Of critical importance, perioperative treatment with the anti-inflammatory drug meloxicam potently inhibited the impact of wounding on tumor growth. Furthermore, our study suggests that the treatment of breast cancer patients with anti-inflammatory agents during and after surgical resection of primary tumors may yield substantial benefits by reducing the incidence of early metastatic relapse.

There seems to be no reason for this not to immediately move into clinical practice, and I hope that this paper gets widely noticed. NSAID therapy is cheap and well-tolerated, and the risk/benefit ratio would seem to be about as good as it can get. So in general, untangling the relationships of the immune system with cancer is continuing to provide results – both in turning the immune response up and (in this case) turning it down. That process is most definitely going to continue. . .


47 comments on “Spreading Cancer (Or Just Waking It Up)”

  1. Who will dig through the data? says:

    Wait. Does that mean that any major wounding is a risk factor for developing metastatic cancer / activating previously asymptomatic tumors?

    1. Fo says:

      Interesting question. With cancer immunotherapy we try to activate the immune system to actually kill tumor cells. However, as we see here, not every form of inflammatory event will lead to the right kind of immune response. The inflammatory events that follow after a major wound can clearly have negative effects on the tumor microenvironment and somehow suppress any potential ongoing immune response against existing (early) tumors there, leading to more favourable conditions for the tumor.

    2. Camptown PI says:

      You really need to pushing your grad students harder…..i mean regret they joined your lab harder. You have goid ideas but if you want to make a company you need a few workhorses that regret everyday they were born.

  2. ScientistSailor says:

    Is there anyone who has surgery who isn’t treated with NSAIDs?

    1. AQR says:

      Yes. Following hip replacement surgery, I was told not to take NSAIDs for six months. I was told that NSAIDs can prevent the infiltration of bone cells into the metal mesh of the prosthesis and thereby prevent the necessary “binding” of the new hip joint to the pelvis and femur. What pain I experienced for the first week was easily controlled by acetaminophen and codeine.

    2. loupgarous says:

      After cancer surgery I was sent back home with tramadol and gabapentin, which is actually a good combo, not as obtunding as morphine sulfate, oxycodone, hydrocodone, or fentanyl. I enjoy life more when I’m as full-on mentally as I can be, and that new combo’s great, along with Voltaren gel for the arthritis and breakthrough cancer pain.

    3. Falanx says:

      Hundreds of people in the UK. GPs here are pathologically resistant to suggest antinflammatories, for some reason insisting that non-NSAID analgaesics, usually opiates, are the only solution. And pharmacists curse them for it. They’re quite happy to give you enough cocodamol to box your liver, but soil themselves over the risks of ibuprofen.

  3. ScientistSailor says:

    … and is the effect limited to meloxicam, or does naproxen show same effect?

  4. Bob says:

    Hope this paper will not end up to be another retraction by Weinberg.

  5. Anon says:

    We have two opposing effects:

    1. Digging around and potentially dislodging more cells with surgery (which certainly won’t actively dislodge fewer cells!)
    2. Reducing the number of cells that could be dislodged naturally following surgery.

    The only way to test which one wins out is to compare rates of metastasis with vs without surgery (perhaps with drugs instead) over time, but surely getting rid of the tumour one way or another will win out in the long run.

    1. ShebW says:

      I wonder how you’d set up your control group, surely, the patients that undergo surgery are a different bunch from the ones that don’t.

  6. Mike says:

    Whatever….almost all surgery follow NSAID (even used before surgery by many for non-surgical pains), yet I have personally seen three of my relatives who after surgery could not survive even months….with research knowing bits and pieces of what happens in human bodies in a disease state (that may also be wrongly interpreted with so complex human biology and unreliable models used in studies), its just luck for post-surgery cancer patients to survive little more and may be little more…

  7. oncodoc (emeritus) says:

    I am an aged, retired oncologist. Recurrences in the surgical site have been a recognized issue in breast cancer surgery since the beginning of the current surgical era. The commonplace explanation was that this was the result of direct shedding of cells by the neoplasm and their implantation. This led to more radical surgeries and post-operative radiation. However, I recollect that there have been studies showing recurrences at remote sites; there have been experiments where mice had surgical wounds placed at a remote site when having mammary cancer procedures, and they did develop disease in the remote scars. I recall that wound healing cell growth factors including the Erb family were implicated.

  8. Marcin RN says:

    Strikes very close to home. Believe it or not – NSAIDs are not used very much at all in the post-surgery floor during first 2-3 postop days. Acetaminophen and opiates – yes. NSAIDs might be a part of a regimen for a discharge.

    1. anon says:

      I would understand why one would use opiates for the first couple postop days, but I fail to see the reason why Acetaminophen is still so widely used.
      It is toxic to the liver, and at least in my personal experience much less effective for pain (and fever) than ibuprofen, which is just as cheap and usually very safe. The only reason I can see why one would use acetaminophen instead of ibuprofen is if there is a severe risk of GI issues, or other hard contraindications.

      1. Marcin RN says:

        NSAID’s carry a bleeding risk that is real. Toxicity of acetaminophen does not happen with proper dosing, which is assured in the hospital setting. Risk/benefit ratio

        1. Falanx says:

          And you could say exactly the same for NSAIDs. Dose makes the poison. Yet everyone’s happy to throw codeine and acetaminophen down the throats of Wilson’s patients without a second thought.

      2. Chris Phoenix says:

        I’ve read that ibuprofen is not as safe for geriatric people.
        higher risk of adverse events… AGS recommends avoiding… “extreme caution”…

      3. Mela says:

        Why aren’t scientists in charge? There is ample scholarly evidence as to Turmeric and others used for millenia like Boswellia… I agree that meloxicam is hazardous to the guts… From personal life altering car crash experience. Opiates are a nightmare, literally as well as figuratively. Why is our world not looking to the pure old forms of healing process with long term benefits? Big3greedy: pharmaceutical and government and agriculture wouldn’t stand for it?

        1. Design Monkey says:

          It’s a free country, mela. If you like to doctor yourself with Turmeric, you can do it as you wish. No pill police will come to stuff you with aspirin instead. Nobody cares about your kooky notions and how fast you will off yourself.

          Now the question is why mela so wants to push her Turmericies on others? Greedy mela’s Turmeric selling business not going well?

        2. loupgarous says:

          Mela, apart from pay-to-publish journals, the clinical literature on turmeric is largely from one team at M.D. Anderson Cancer Center in Houston, Texas. And the prime investigator on that team’s been snarled up in allegations of research misconduct, so the Western medical consensus on turmeric is anything but clear-cut.

          I took turmeric for general health reasons, and didn’t notice much difference. Ginger seems to help me as much as Phenergan for nausea, however.

          1. Gordonjcp says:

            Turmeric and ginger are great. I strongly recommend them, and they’re very easy to get hold of and try for yourself.

            They really one of the best ways to make your curry taste good.

        3. Pennpenn says:

          Because those “old and pure” processes often don’t work, don’t have any mechanism by which they could work, and are most often pushed by hacks, quacks, and frauds. Just because something is old or “pure” (whatever that means) doesn’t mean it works.

          1. Hannah says:

            @Pennpenn, those things did work for thousands of years, and that’s part of how we have survived to the “modern” age. It could well be that the toxicity in our bodies due to food additives, agricultural poisons, and the overall toxicity in our air, water and soil—combined with our increasingly unnatural lifestyle— is what causes decreased effectiveness in some people. I’ve been taking Turmeric and it has reduced my cholesterol levels significantly in a reasonably short period of time with zero side effects. There is a reason that cancer and other autoimmune diseases are often referred to as “diseases of civilization.” But, since any pharmacist (and some doctors as well) will tell you that every drug began as a molecule found in a plant, there’s no reason why people should have to accept or endure derision for going straight to the source for assistance with their health conditions.

          2. Pennpenn says:

            @Hannah The notion that “any pharmacist (and some doctors as well) will tell you that every drug began as a molecule found in a plant” is sketchy at best, and given that even if they’re sourced from plants in basically all cases they’ve been changed and processed into the effectual forms they have now means that “going to the source” is akin to thinking that eating wheat off the stalk is the same as bread.

            That and lifespans and general health have been improving in many ways since we started dropping many of the “old and pure” notions (where we didn’t incorporate the ones that did work), and we can live long enough for other conditions to come up (conditions that probably would have been hidden or irrelevant compared to poxes or polio previously).

            I’m not saying there aren’t things in the modern world that are doing us harm, but the only way we’re going to deal with that is understanding the mechanisms behind them and correcting those problems- not pretending that “old ways are best ways”. Since they’re really not.

    2. Michael T says:

      Part of the reason that NSAIDs are not prescribed post-surgically is that they have some anti-platelet activity, so there is an increased risk of bleeding. I agree that the risk of metastasis far outweighs the bleeding risk though.

  9. JimF says:

    With breast cancer, there is often a combination of surgery, radiation and tumor-specific and nonspecific chemotherapy.
    In the case where surgery and nonspecific chemotherapy are called for, there is a big split about which to do first.
    I have to think about what I would recommend if the results from this paper bear out.
    What do others think?

  10. Peter Shenkin says:

    It’s been noted that despite increases in early screening for breast cancer, and concommitant early surgery, mortality rates for breast cancer have remained constant. Why has been a mystery. It’s possible that this observation might offer both explanation and at least a partial fix.

    If surgery has in fact increases metastasis, this could explain why, despite early surgical intervention, mortality rates have not gone down. And if post-surgical NSAIDs can prevent or reduce the metastasis, then their routine use could result in the decrease in mortality that has been elusive up to now.

  11. Barry says:

    Anyone trying to get discharged from a U.S. hospital after even minor surgery will have learned that it’s hard if not impossible to get an ibuprofen. They’ll push morphine, or acetaminophen, or vicodin on you. But not ibuprofen. Oddly, as long as you have a line in, you can get toradol (ketorolac).
    Clinical evidence that acetamiophen relieves pain is spotty. Its toxicity however is well documented.

    1. AH says:

      Ibuprofen is OTC.

    2. loupgarous says: says “There are several potential pharmacokinetic benefits of IV acetaminophen. The time to peak analgesic effect of IV acetaminophen is within 10 minutes after its administration compared with 1 hour for oral acetaminophen. It is also associated with significantly higher mean cerebrospinal fluid concentrations than oral or rectal formulations (2). This makes it well suited for settings where quick analgesia is required, such as the perioperative period, especially since the duration of action appears to be the same between both formulations (4 to 6 hours). IV acetaminophen has better bioavailability when gastric function is compromised (i.e. post-operative ileus) (3). Finally, due to differences in first pass metabolism, IV acetaminophen may expose the liver to 50% less initial acetaminophen (4).”

      Reviews of the literature are less emphatic about the case for IV acetaminophen, but an ER doc I know says its bioavailability is great that way and toxicity is diminished. But the IV formulation costs much, much more than oral APAP.

  12. Jackie says:

    This article boarders on conspiracy theory, but thank god pipeliners have finally thought in that area that lies beyond the military-industrial-pharma complex, which holds that cancer is chemical and only chemical, to be treated only by you guessed it more chemicals.

    1. Pennpenn says:

      How could it be anything but a chemical construct? And how would you treat it in any way that didn’t include varying the chemical context of the tumors?

      Or did you mean “Chemicals” in the same manner as people talking about “organic” foods?

  13. For a case where surgery does seem to spread cancer, look up the hysterectomy morcellator controversy. That’s perhaps the worst-case scenario for surgical cancer spread: instead of removing the uterus whole, it’s chopped up into tiny pieces so that it can be sucked out through a small tube. Though still controversial, it’s gotten to the point of an FDA warning.

    1. NJBiologist says:

      It’s beyond that–JNJ withdrew the Ethicon morcellator some time around 2015.

  14. I wonder about the role of transforming growth factor beta (TGFbeta), which plays a critical role in wound healing, but also assists in modifying the tumour microenviroment and stroma, in part through action on cancer-associated fibroblasts, as well as being immuosuppressive.

    Lilly have a couple of small molecule inhibitors in Phase I/II studies, in combination with immune checkpoint inhibitors.

  15. Anonymous says:

    Around 10 years ago, I was at seminar and spoke to a Harvard Med School who was promoting the successful use of anti-inflammatories in cancer surgeries. He said they had clinical data to back it up but not a full clinical trial … partially because they couldn’t get it funded. (The paper cited by Derek is Harvard-MIT but I don’t remember if it’s the same Harvard group.)

    An Israeli group reported something similar late ’17 or early ’18. The “news” version of that paper had an interview with the PI who said that they have been studying anti-inflammatories and cancer surgery for 25 years (but I don’t have lit access to check that claim).

    The basic idea has been around for decades. I am sure that much is in the details.

    1. Camptown PIs says:

      You really need to open up a can of whoop as on your students. If they have had 10-20 years with this idea and still have not gotten you a shiny new company, there is a problem.

  16. Barry says:

    The lower incidence of colon cancer in chronic users of NSAIDs motivated Merck’s big (disastrous) trial of Vioxx over a decade ago. The effect is real, but the increased cardiac risk is not worth it.

    1. kismet says:

      That is only true in primary prevention settings I think. Risk benefit ratio for secondary prevention post surgery might be better.

  17. Scott says:

    That is one of the weirdest things I’ve read…

    It’s tough to get an OTC medicine when you’re hospitalized (been there too many times for kidney stones). Also, the docs order me to not take any NSAIDs for a week or more before surgery.

    After I broke my back, the doc gave me Vioxx. Worked wonders to knock the pain down. Think I was on Vioxx for a single month before approval got yanked. Now I’m on a massive mix of pain pills including Tramadol and Meloxicam. I can’t take ibuprophen, I was taking so much just after I’d broken my back that any amount now triggers instant heartburn.

  18. loupgarous says:

    I have metastatic paraganglioma. It went from the initial tumor excision site between the heart and spleed to my liver (I have NAFLD), and from there through the lymph nodes to my stomach, thence to where I have degenerative joint disease – the acetabulum on one hip, one of my vertebrae (I have widely disseminated DISH syndrome in the spine and elsewhere) and near the hinge of my jaw. The metastases do tend to head for tissue in the process of healing from injury or being injured.

  19. milkshake says:

    This is potentially a huge discovery if re-confirmed (and meloxicam is probably the best NSAID currently on the market).

    Even back in late 90s, I heard about the effect of resection of the primary tumor greatly accelerating the growth of metastases, and that micro-metastases were somehow kept in check by the primary tumor – but the effect was (back then) explained by massive local over-secretion of growth factors and angiogenesis within the primary tumor site (which brought about their global down-regulation by a feedback loop elsewhere), etc. It wasn’t attributed to the immune response at the time, and the whole mechanism was mysterious.

    So this is a great explanation. Apart from a simple method of lowering the risk of metastatic growth, it could outright provide a new target for the immunotherapy of cancer.

  20. DrOcto says:

    Sadly once this excellent work gets through all the media filters, the headline will read ”Asprin may cause cancer”

  21. Survivor says:

    This effect is also known for the NSAID ketorolac.
    There is a clinical trial for its administration peri-operatively.
    But try as I might, I could not get my surgical team to administer ketorolac perioperitervely before my recent mastectomy for breast cancer. And, for sure, I was not allowed to take any NSAIDs in my hospital stay afterwards (which, unfortunately was long because of complications).

  22. Harri says:

    I wonder if this mechanism explains all those positive results obtained with mouse models of cancer that never translate it to a positive clinical outcome? Anything that can limit the initial inflammatory response in mice associated with the introduction of tumor cells will also limit the tumor growth & spread?

  23. I have been involved in this research for some years and can address a few questions raised.
    A book was published last year on this topic. The main chapter is available open access as Harvard Dash. “Perioperative Inflammation as Triggering Origin of Metastasis Development”, Michael Retsky and Romano Demicheli.

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