Does the Agent Influence Tumours?

Anaesthesia has big impacts, but could it be that the clever drugs add major risks? A post from Andrew Weatherall

Anaesthesia can be a specialty of the briefest touches. There are plenty of patients who we’ll meet once and that’s that. If you’re reading this you probably think it’s a pretty important one off meeting but it’s still a short moment. Except at a lot of paediatric hospitals you get to know some patients because they keep coming back. One of those groups is the cancer kids.

They come at the time of diagnosis. They return for staging. They need central venous access. Some need resection. Some of them need all the big needles for marrow or spinal fluid. So many needles.

Of course for frequent flyers the quality of the care we give matters a lot. So I’m sure everyone thinks carefully about their assessment, induction, the wake up and any analgesic requirements along with all the other little details that the patient needs us to. We’re all about the details.

So here’s a detail we might want to think about that’s cropping up in the adult literature: does the agent you choose matter in cancer recurrence?

 

Making Sense of Things That Make Not Much Sense

This topic came up as a bit of a tangent from a paper that cropped up recently in Anaesthesia with the catchy title “Effects of anaesthesia on proliferation, invasion and apoptosis of LoVo colon cancer cells in vitro”. Yes, the “vitro” bit means lab glasswork, microscopes and the word serum feature heavily but this isn’t the first thing that’s popped up in the area.

In this particular study the aim was to look at the changes in the serum you might see with propofol/regional anaesthesia vs a sevoflurane/opioid cocktail. Why would you bother with that? Fair question.

We’re all familiar with the cancer master plan involving local spread, followed by intravascular invasion and day tripping to some other distant organ (except the day trip turns into a nasty home occupation situation). It doesn’t take much imagination to figure that immune cytokine signalling and alterations in apoptosis could be part of letting those cells get out of control. That’s part of the becoming invasive bit and you can look for evidence of this in the lab.

It’s also worth remembering that in the perioperative period the combination of a degree of immunosuppression and surgical stress response might influence the functioning of the immune system at a time when you’ve just liberated tiny deposits of cancer cells. So if your underlying question is “does the anaesthetic approach influence cancer recurrence?” then it might be reasonable to look at markers of a different inflammatory response. In this study they looked at the neutrophil/lymphocyte ratio (which they call the NLR but I already use that acronym for a “No Lederhosen Restaurants” activism group so it’s a real struggle).

So take serum pre- and post-open colon cancer surgery having the different anaesthetic recipes, use it to bathe LoVo cancer cells (all derived from a metastasis from a 56 year old man) and watch the tourism behaviour of those cells and you have this study.

 

So …?

At baseline prior to the surgery the serum was about the same. 24 hours after surgery those having the regional plus propofol option had much less active serum-bathed LoVo cells – they were less invasive, less likely to be viable and that NLR was lower too, indicating a less inflammatory serum soup.

So where does that all fit?

Well, there’s some other work around the labs which is a little interesting. Isoflurane can increase tumour growth of a line of human cancer cells. Propofol doesn’t. It might even kill cancer cells. The same crew who published this study have previously shown that the serum of those on the propofol-regional train has fewer angiogenesis-promoting factors.

Local anaesthetic might just kill cancer cells directly too (though whether that’s how it is in vivo is a bit less clear). Why would local anaesthetic even have any particular interaction with cancer cells? Well it turns out there are voltage-gated ion channels on a lot of different tumour cells (breast, cervical, colon, lung, skin, ovarian  and prostate).

The use of local anaesthetic and paravertebral regional analagesia have been found to reduce breast cancer recurrence rates compared to those having general anaesthesia and morphine. In one clinical study related to prostate cancer, the use of local anaestheic and epidural analgesia was associated with a 57% lower recurrence rate after radical prostatectomy (again compared to GA and morphine and we’re talking biochemical recurrence). There are similar findings for melanoma patients.

Adventures of KM & G-Morris

Yes, I agree there’s a lot to lie back and think about.

Put away the volatile then?

Well, that might be a little premature. Unsurprisingly, not all studies looking at this stuff show such associations. One study in colon cancer suggested improved survival with epidural anaesthesia only in patients over 64. Huh? Is that a Beatles reference from malignant neoplasms?

Meta-analyses haven’t shown a difference in cancer recurrence so far. Meanwhile propofol may have advantageous immunomodulation effects compared to volatiles, but a lot of that is based on pre-clinical work. That’s early days though.

So we have things that might show associations in retrospective work, but not so much in meta-analyses added to mechanisms we don’t quite understand that we’re still figuring out from pre-clinical data that’s interesting but not really settled.

It’s a big call to say everyone should ditch the vapourisers.

 

Wait, this site is about kids’ anaesthesia, what about that?

Yes, those are a lot of older people’s cancers. The question is will that be all we get? This is the recurrent problem in all things kids. Will we get research directly relevant to our patients?

The originating cells for paediatric solid organ tumours aren’t the same. These sorts of paediatric tumour aren’t common. The outcomes are mostly better than adult malignancies. These are elements that make research to provide meaningful associations even harder than the already slightly confusing figures for adults.

The adult work doesn’t even touch on some of the things that matter in kids either. Adults don’t tend to get repeated general anaesthetics as part of treatment with haematological conditions, as one simple example. There’s not really any evidence for that stuff.

At the same time, if there is any elevated risk created by our anaesthetic choices, don’t those kids have a long life of carrying that around?

A little like animal research in the area of neurotoxicity made us keen to look further, maybe the hints from the adult literature should make us want to explore this problem in a way that is meaningful for paediatric patients.

In the meantime you can make perfectly rational arguments to use TIVA or volatile and opioids or regional approaches. There’s not enough evidence directly on this question to make it change practice.

Alternatively, you might choose the bonus principle in making choices – “Well there are these other pretty good reasons to choose TIVA (or regional) and there’s this outside chance that it matters for malignancy risk but even if it that turns out to be something that’s not a thing, I don’t lose out by going down the TIVA/regional path and it might just be a bonus”.

The thought process anaesthetists use to make a choice would need a completely different chat. Meanwhile, we come to a familiar refrain: we need to experiment more on kids.

Wait, that sounded bad.

We need more research. And No Lederhosen Restaurants.

 

Notes: 

That otter comes from the flickr Creative Commons area. It’s unaltered and was put there by “Adventures of KM & G-Morris”.

Want to do some more reading?

Here’s the paper mentioned in Anaesthesia

Xu YJ, Li SY, Cheng Q, Chen WK, Wang SL, Ren Y, Miao CH. Effects of anaesthesia on proliferation, invasion and apoptosis of LoVo colon cancer cells in vitro. 2016;71:147-54.

and the editorial to go with it:

Ciechanowicz SJ, Ma D. Anaesthesia for oncological surgery – can it really influence cancer recurrence? Anaesthesia 2016;71:127-31.

Here’s a good thing about the local anaesthetic stuff (and it’s free to access, even better):

Fraser SP, Foo I, Djamgoz MBA. Local anaesthetic use in cancer surgery and disease recurrence: role of voltage-gated sodium channels? BJA. 2014;113:899-902. 

Meanwhile, here’s a plug for a podcast we did on the topic of TIVA in kids featuring Dr Justin Skowno. It’s here.

If you think stuff on here is interesting, there’s a spot on the stage where you can set yourself up to follow so you’ll receive a notification whenever something new pops up. Finally, a request for help – we’re always keen to hear comments and feedback. We’d like to make the site as good as we can.

 

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One response to “Does the Agent Influence Tumours?

  1. Pingback: Does the Agent Influence Tumours? | Prehospital and Retrieval Medicine - THE PHARM dedicated to the memory of Dr John Hinds·

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