Wednesday, 18 September 2013

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.

Of course this has enormous implications for screening of the general population. One of the biggest controversies in oncology is about mammographic screening (an issue discussed here: http://www.anticancer.org.uk/2013/07/book-review-mammography-screening-truth.html). Here was a possible explanation for the finding that screening leads to over-diagnosis and the deaths of women who would not otherwise have died from breast cancer or the result of breast cancer treatment. Unfortunately this is another inconvenient result and the authors suddenly found themselves on the receiving end of some unpleasant treatment. As the paper states:
Meanwhile, we were publishing papers and submitting grant proposals to support our research. As evidence of the soundness of our findings, we naively reported that based on clinical data we could quantitatively explain the mammography paradox. But this tactic apparently backfired. Our proposals did not survive triage. As an apparent result, there was an unpleasant span of years during which we had no financial support. This was a low spot in our research. The simulation research that was conducted in the US was halted (but the clinical research continued in Italy) and we continued to publish papers. We report this since researchers intending to conduct translational research should be aware that their findings might intentionally or unintentionally trespass on sensitive terrain with unfavorable results.

As in climate science, it seems as though some results that stray from the ‘consensus’ are not acceptable, even though they are based on sound science and observation. For those of us who believe in the scientific method this is a depressing state of affairs to say the least.

However, thanks to the work of one anesthiologist (Dr Patrice Forget) working in a Belgian hospital new data published in 2010 cast a new light on this pattern of relapse. While most anesthetists only track patients in the immediate period after surgery, Dr Forget went back and looked at the pattern of breast cancer relapse in the four years after treatment and then correlated this with the different drugs that were used. And the surprising result, since replicated with updated data, was that treatment with the low-cost pain-killer ketorolac (related to the over-the-counter drug diclofenac), had a significantly different outcome to treatment with alternative drugs. In fact the four year relapse pattern was all but absent in the patients given ketorolac.
Now that is a result that is stunning in its clinical implications. It suggests that a simple change in treatment protocols for women undergoing mastectomy can lead to a big reduction in cancer relapse and metastases. This is a phenomenal finding.

The obvious next step is to perform a randomised controlled trial so that the effect can be compared after the event rather than being something found by looking at old data. And thanks to the support of the cancer charity Reliable Cancer Therapies, such a trial is actually going to take place. Details can be found here: http://clinicaltrials.gov/ct2/show/NCT01806259

There is much more to say about this work, but for now this is one of the most positive developments I have seen in a while.

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