Q & A With Dr Patrice Forget: Ketorolac and Breast Cancer

In the previous article on this site I wrote about recent work that showed that the use of a cheap, safe and generally available anti-inflammatory pain killer (ketorolac) had the potential to massively reduce the incidence of cancer relapse following surgery. This extraordinary result was discovered by a Belgian anaesthesiologist Dr Patric Forget and colleagues. Now working on a clinical trial to put this finding under test, Dr Forget kindly agreed to respond to a short interview to give us more of background to his research.

PP: What prompted your initial investigations - did you expect to find the results that you found?

PF: The diverse long term effects of anaesthetic techniques and analgesic medications have been suspected for many years. Discrepancies exist about the effect on outcome in humans. Concerning opioids, many data exist, but results are inconsistent. Concerning NSAIDs, animal data are consistent, but no human data are available. Therefore, we investigated it in the prospective patients listing existing in our Cancer Centre. Nevertheless, the magnitude and the repetition of the NSAIDs data were relatively unexpected.

PP: What are the clinical factors that influence the choice of ketorolac versus other medications?

PF: The anaesthesiologists have to make choices for which there are not always evidence-based guidelines. This is the case with single NSAIDs dose in the perioperative period. The usefulness of this single dose in terms of analgesia improvement is still matter of debate. The American Society of Anesthesiology has no definitive recommendations about it. Consequently, in many centres, including ours, some anaesthesiologists use it systematically, and others not.

PP: Your findings suggest that other interventions - such as taking a surgical biopsy - could also have a negative influence on cancer outcomes. What is your view on this?

PF: Inflammatory pathways are implicated in the development of cancer. It is probable that the degree of tissue injury during surgery is associated with cancer outcome. Nevertheless, whether  this effect is mediated by an influence on tumours cells, tumours cells spreading and/or immune suppression is not clear. In all cases, many arguments exist to limit as far as possible the extent of tissue attrition and surgical procedures in cancer patients.

PP: Although the emphasis of your work is on breast cancer, there is evidence that a similar bimodal pattern of relapse occurs in other cancers. Do you think that peri-operative ketorolac can have a similar reduction in relapse in these cancers?

PF: Yes. We have done the same observation in non-small cell lung cancer (NSCLC) (Forget et al, Ann Surg Oncol 2013). In NSCLC, the bimodal pattern of relapse was shown by Demicheli et al. Out data shows that the NSAIDs effect is also present. In contrast, in prostate cancer, no NSAIDs effect was observed (Forget et al, Eur J Anaesthesiol 2011). Concommitantly, no bimodal patter of relapse was shown, in my knowledge, arguing for a different pre-, intra- and/or postoperative cancer pathophysiology.

Ketorolac and Breast Cancer

Most cancer papers, even the ones with really interesting and important results, are not exactly an easy read. Aside from the technical content, they’re written in a deliberately dry and unemotional style that suggests objectivity and cautiousness. Which is why the paper ‘Promising development from translational or perhaps anti-translational research in breast cancer’, published in the journal Clinical and Translational Medicine stands out from the crowd. It’s an open access paper available here: http://www.clintransmed.com/content/1/1/17. If you only ever read one cancer paper make it this one. It’s written a highly accessible style, raises key questions and contains a result that, if confirmed, could reduce breast cancer mortality by 25% - 50%. That would be a massive step forward, truly massive.

And what is this finding that holds the promise of reducing breast cancer deaths by such a massive amount? It’s not a new drug, not a new form of therapy not even a new type of treatment. It’s simple, cheap and easily available and, best of all, easy to slot into place in existing treatment protocols. The starting point for all of this is the observation that the pattern for cancer recurrence following mastectomy occurs in two waves (it’s bimodal in stats jargon). The first wave happen in the immediate period (the first four years), and then there is a second peak of relapses that happens much later, around six years and stretching out to 10 – 15 years. This pattern of relapse has been confirmed in numerous countries and studies now, and seems to also be common in some other cancers, including prostate, lung, and pancreatic cancer, as well as osteosarcoma and melanoma.

This pattern of relapse could not easily be explained by existing theories of cancer growth. In fact, it was a down-right inconvenient finding with huge and controversial implications. Chief among these was that it suggested that surgery to remove the primary tumour was often triggering spurts of metastatic disease. To quote from the paper directly: Between 50% and 80% of relapses result from surgery initiated growth. That is a truly shocking result. It means that many breast cancer deaths are caused by the surgery meant to remove the initial small tumours.

Aspirin To Treat Liver Tumours?

There were a number of really interesting papers that popped up over the summer, and I'll be blogging about them in the next few days. For today though I'll focus on an open-access paper in the World Journal of Hepatology (and in case you're wondering, hepatology is the branch of medicine focused on the liver, pancreas and gall bladder). The paper is entitled 'In vivo assessment of intratumoral aspirin injection to treat hepatic tumors' and looks at what happens when you inject aspirin directly into liver tumours. Given the very high levels of interest in the anticancer properties of aspirin, taking it to the next level and injecting it directly rather than swallowing it seems such an obvious idea that it's a suprise that no one has tried this. But then it's often the case that it's the simple, obvious ideas that get over-looked.

And the results? Stunning, to be honest. The experiment took place in rabbits implanted with liver tumours and then injected with a solution of sodium bicarbonate and aspirin. Firstly there seemed to be no ill-effects - the rabbits showed no physical changes aside from changes in the tumours injected. And here the results were clear - the tumours collapsed and seven days after the treatment had disappeared completely, whereas in the control group the tumours continued to grow as expected. Furthermore, there was no evidence that the tumours started to recur or regrow.

Clearly this is a small study in rabbits and not humans, but the result is really striking and it cries out for follow up research. Given the low toxicity of aspirin, the obvious follow-up is for a small human trial. If the results are as fast and as positive we should know very quickly whether this is a viable treatment option to explore further.

Unfortunately I've not been able to contact the researchers (in Brazil), but hopefully this isn't destined to be one of those interesting results that sits languishing on the shelves and goes no where.